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Vol. 39 Supp. 1 June 2021
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Articles from the 16th International Conference on Malignant Lymphoma,
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University Hospital Großhadern
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Current Treatment Landscape and Emerging
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Gilles Salles, MD, PhD
Memorial Sloan Kettering Cancer Center
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The Evolving Therapeutic Options for Patients
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Pier Luigi Zinzani, MD, PhD
University of Bologna
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Hematological Oncology
Vol. 39 Suppl. 1 June 2021
16th Internaonal Conference on Malignant Lymphoma
Contents
MEET THE PROFESSOR ARTICLES
EDUCATIONAL SYMPOSIUM ARTICLES
Educaonal symposium on High risk follicular lymphoma
Educaonal symposium on Immunotherapy
Please Visit www.daiichisankyo.com
to Explore Our Oncology Pipeline
Daiichi Sankyo Europe GmbH, Zielstattstr. 48, 81379 Munich, Germany.
© 2021 Daiichi Sankyo Europe GmbH. All Rights Reserved. GLM-GCS-MONC-0049 01/21
DOI: 10.1002/hon.2885
SUPPLEMENT ARTICLE
16
th
International Conference on Malignant Lymphoma
Virtual Edition 18 ‐22 June, 2021
Organized by the Foundation for the Institute of Oncology Research (IOR) in cooperation with the American Association for Cancer Research
(AACR)
Note: The articles published in the 16‐ICML Educational Book represent the presentations made at the “Meet the Professor” sessions and
“Educational Symposia” during the 16th International Conference on Malignant Lymphoma (16‐ICML Virtual Edition ‐Lugano, Switzerland) on
June 18‐22, 2021.
All manuscripts submitted have been subjected to peer review, and authors have been requested to disclose any relationships with the
companies whose products or services are discussed in their manuscripts.
The 16‐ICML Educational Book production has been supported by an unrestricted educational grant of BeiGene.
Disclaimer: This Educational Book and the Abstract Book have been produced using author‐supplied copy. Editing has been restricted to some
corrections of spelling and style where appropriate. No responsibility is assumed for any claims, instructions, methods or drug dosages contained
in the articles and abstracts: it is recommended that these are verified independently.
Hematological Oncology. 2021;39(S1):7–14. wileyonlinelibrary.com/journal/hon © 2021 John Wiley & Sons Ltd.
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ACKNOWLEDGEMENTS
INTERNATIONAL CONFERENCE ON MALIGNANT LYMPHOMA (ICML) and FOUNDATION FOR THE INSTITUTE OF ONCOLOGY
RESEARCH (IOR) PRESIDENT
Franco Cavalli, Bellinzona (Switzerland)
ICML ORGANIZING COMMITTEE CHAIRMAN
Francesco Bertoni, Bellinzona (Switzerland)
ICML ORGANIZING COMMITTEE
(based in Bellinzona)
Michele Ghielmini
Alden Moccia
Bertrand Nadel, Marseilles (France) ‐Representative of American Association for Cancer Research (AACR)
Fedro Peccatori, Milan (Italy) ‐Representative of European School of Oncology (ESO)
Davide Robbiani
Davide Rossi
Anastasios Stathis
Georg Stüssi
Emanuele Zucca
16‐ICML ADVISORY BOARD
James O. Armitage, Omaha, NE (USA) ‐CHAIRMAN
Elias Campo, Barcelona (Spain)
Bruce D. Cheson, Washington, D.C. (USA)
Nicholas Chiorazzi, Manhasset, NY (USA)
Wee Joo Chng, Singapore (Singapore) Riccardo Dalla‐Favera, New York, NY (USA)
Stephan Dirnhofer, Basel (Switzerland)
Martin Dreyling, Munich (Germany)
Jonathan W. Friedberg, Rochester, NY (USA)
Gianluca Gaidano, Novara (Italy)
Philippe Gaulard, Créteil (France)
Mary K. Gospodarowicz, Toronto, ON (Canada)
Peter W.M. Johnson, Southampton (UK)
Brad S. Kahl, St. Louis, MO (USA)Ralf K üppers, Essen (Germany)
John P. Leonard, New York, NY (USA)
T. Andrew Lister, London (UK)
Markus G. Manz, Zurich (Switzerland)
Ari M. Melnick, New York, NY (USA)
Koichi Ohshima, Kurume (Japan)
Astrid Pavlovsky, Buenos Aires (Argentina)
Leticia Quintanilla‐Martinez de Fend, Tübingen (Germany)
S.Vincent Rajkumar, Rochester, MN (USA)
Kerry J. Savage, Vancouver BC (Canada)
John F. Seymour, Melbourne (Australia)
Margaret A. Shipp, Boston, MA (USA)
Lena Specht, Copenhagen (Denmark)
Catherine Thieblemont, Paris (France)
Pier Luigi Zinzani, Bologna (Italy)
Wilhelm Wössmann, Hamburg (Germany)
Weili Zhao, Shangai (China)
8
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CONFERENCE SECRETARIAT
Cristiana Brentan, Federica Cariglia, Angela Kurtz, Orietta Lugli, Chiara Saporiti
Foundation for the Institute of Oncology Research (IOR)
Via Vela 6, CH‐6500 Bellinzona
The Organizers would like to express their sincere gratitude to the Industry Partners who continue to support the Conference. Their unre-
stricted support is essential to the dissemination of the Scientific and Industry programs to the worldwide community engaged in the study and
treatment of lymphoid neoplasms:
AbbVie, Inc.
Acrotech Biopharma LLC
ADC Therapeutics
AstraZeneca
Bayer
BeiGene
Bristol Myers Squibb
Clinigen
CRISPR Therapeutics
Daiichi Sankyo
F. Hoffmann‐La Roche
Genmab
Gilead Sciences Europe Ltd.
HTG Molecular Diagnostics
Incyte
Janssen Oncology Pharmaceutical Companies of Johnson & Johnson
Karyopharm
Loxo Oncology at Lilly
Lymphoma Hub
Miltenyi Biomedicine
MorphoSys
MSD
Novartis Oncology
Pfizer Oncology Regeneron
Takeda Oncology
(updated on May 2021)
The Organizers would like to express their sincere gratitude to the following Partners for their precious support, essential to the organization of
this Virtual edition of the Conference and to the achievement of its objectives:
American Association for Cancer Research – AACR
City of Lugano
European School of Oncology – ESO
European School of Oncology Foundation – ESOF
European Society for Medical Oncology – ESMO
IBSA Foundation for Scientific Research
International Extranodal Lymphoma Study Group ‐IELSG
International Lymphoma Radiation Oncology Group ‐ILROG
Lymphoma Coalition
Saudi Society of Blood & Marrow Transplantation ‐SS‐BMT
Swiss Cancer Research Foundation
Union for China Lymphoma Investigators – UCLI
Università della Svizzera Italiana ‐USI
(updated on May 2021)
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9
10
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SCIENTIFIC PROGRAM ‐MEET THE PROFESSOR SESSION AND EDUCATIONAL SYMPOSIUM SCHEDULE
All session times for the 16‐ICML are Central European Summer Time (CEST)
Saturday, June 19, 2021
Time Channel Session Article/ abstract nr.
13:00 – 13:30 Channel 1 “Meet the Professor” session
What's new in peripheral T‐cell lymphomas EB 06
Stefano Luminari, Reggio Emilia (Italy)
13:30 – 13:45 Live Q&A
13:00 – 13:30 Channel 2 “Meet the Professor” session
Cutaneous T‐cell lymphoma – an update 2021 EB 05
Werner Kempf, Zürich (CH)
13:30 – 13:45 Live Q&A
13:00 – 13:30 Channel 3 “Meet the Professor” session
Personalized medicine for Hodgkin lymphoma: mitigating toxicity while preserving cure EB 04
Peter W.M. Johnson, Southampton (UK)
13:30 – 13:45 Live Q&A
13:00 – 13:30 Channel 4 “Meet the Professor” session
Use of available prognostic scores in treatment decision: beyond standard prognostic
scores to include molecular/genetics/imaging
John F. Seymour, Melbourne (Australia)
13:30 – 13:45 Live Q&A
Sunday, June 20, 2021
Time Channel Session Article/ abstract nr.
15:00 – 16:30 Channel 1 Educational symposium on High risk follicular lymphoma
Co‐chairs: Elias Campo, Barcelona (Spain) and Carla Casulo, Rochester, NY (USA)
15:00 – 15:25 Upfront identification of high risk follicular lymphoma EB 12
Carla Casulo, Rochester, NY (USA)
15:25 – 15:50 Vulnerabilities in the tumor and microenvironment in follicular lymphoma EB 11
Elias Campo, Barcelona (Spain)
15:50 – 16:15 High risk follicular lymphoma: treatment options EB 10
Brad Kahl, Saint Louis, MO (USA)
16:15 – 16:30 Live Q&A
16:45 – 17:15 Channel 1 “Meet the Professor” session
Molecular diagnostics and reporting in lymphoid malignancies: current status and beyond EB 09
Richard Rosenquist Brandell, Stockholm (Sweden)
17:15 – 17:30 Live Q&A
16:45 – 17:15 Channel 2 “Meet the Professor” session
New drugs and pharmacological interactions in real life EB 10
Anastasios Stathis, Bellinzona (CH)
17:15 – 17:30 Live Q&A
16:45 – 17:15 Channel 3 “Meet the Professor” session
Mantle cell lymphoma ‐advances in molecular biology, prognostication and treatment
approaches
EB 03
Martin Dreyling, Munich (Germany)
(Continues)
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11
(Continued)
Sunday, June 20, 2021
Time Channel Session Article/ abstract nr.
17:15 – 17:30 Live Q&A
16:45 – 17:15 Channel 4 “Meet the Professor” session
Recognizing but not harming. Borderline B‐cell lymphoid proliferations EB 07
Leticia Quintanilla‐Martinez de Fend, Tübingen (Germany)
17:15 – 17:30 Live Q&A
Monday, June 21, 2021
Time Channel Session Article/ abstract nr.
15:00 – 16:30 Channel 1 Educational symposium on Immunotherapy
Chair:
15:00 – 15:25 Optimizing CAR T‐cell therapy in lymphoma EB 15
Gilles Salles, New York, NY (USA)
15:25 – 15:50 Allogeneic stem cell transplant in non‐Hodgkin lymphomas: still an indication? EB 14
Peter Dreger, Heidelberg (Germany)
15:50 – 16:15 Bi‐specific antibodies for the treatment of lymphoma: promises and challenges EB 16
Stephen J. Schuster, Philadelphia, PA (USA)
16:15 – 16:30 Live Q&A
18:00 – 18:30 Channel 1 “Meet the Professor” session
Sequencing of myeloma therapy: finding the right path among many standards EB 08
S. Vincent Rajkumar, Rochester, MN (USA)
18:30 – 18:45 Live Q&A
18:00 – 18:30 Channel 2 “Meet the Professor” session
Langerhans Cell Histiocytosis: Version 2021 EB 01
Carl E. Allen, Houston, TX (USA)
18:30 – 18:45 Live Q&A
18:00 – 18:30 Channel 3 “Meet the Professor” session
Molecular classification of aggressive lymphomas – past, present, future EB 02
Björn Chapuy, Göttingen (Germany)
18:30 – 18:45 Live Q&A
12
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INDUSTRY PROGRAM – SATELLITE SYMPOSIUM SCHEDULE
Friday, June 18, 2021
12:00 – 13:30 Channel 1 Janssen Oncology Pharmaceutical Companies of Johnson & Johnson
PRECISION MEDICINE IN LYMPHOMA: WHAT DOES IT MEAN?
Chair: John Gribben, London (UK)
12:00 – 13:30 Channel 2 AstraZeneca
EVOLVING STRATEGIES USING BTK INHIBITORS IN CLL: A SELECTIVE APPROACH TO
IMPROVE PATIENT OUTCOMES
Chair: Paolo Ghia, Milan (Italy)
12:00 – 13:30 Channel 3 MSD
EXPLORING THE UTILITY OF NOVEL TARGETS IN LYMPHOMAS
Chair: Ulrich Jaeger, Vienna (Austria)
12:00 – 13:30 Channel 4 ADC Therapeutics
ELEVATE YOUR KNOWLEDGE ON NOVEL ANTIBODY‐BASED THERAPIES TO TREAT
R/R DLBCL
Chair: Carmelo Carlo‐Stella, Milan (Italy)
14:00 – 15:30 Channel 1 Bristol Myers Squibb
ARE WE GOING TOWARDS A NEW CARE PARADIGM IN FL AND CLL?
Chair: Stefano Luminari, Reggio Emilia (Italy)
14:00 – 15:30 Channel 2 Medscape (supported by an independent educational grant from Takeda)
SPOTLIGHT ON LYMPHOMA: ADDRESSING REAL WORLD CLINICAL CHALLENGES
FOR HL AND PTCL
Moderator: Timothy Illidge, Manchester (UK)
14:00 – 15:30 Channel 3 AbbVie
NOT ALL BISPECIFIC ANTIBODIES ARE CREATED EQUAL
Chair: Gilles Salles, New York, NY (USA)
14:00 – 15:30 Channel 4 Pfizer Oncology
COVID‐19 IN CLL AND B CELL MALIGNANCIES
Chair: Anthony Mato, New York, NY (USA)
16:00 ‐17:30 Channel 1 Kite, a Gilead Company
BUILDING ON SURVIVAL IN CELL THERAPY: FOCUS ON THE FUTURE
Chair: John Gribben, London (UK)
16:00 ‐17:30 Channel 2 Incyte
PEARLS OF KNOWLEDGE: EXPERT PERSPECTIVES IN THE TREATMENT OF R/R DLBCL
16:00 ‐17:30 Channel 3 Regeneron
EVOLVING TREATMENT PARADIGM FOR RELAPSED/REFRACTORY DIFFUSE LARGE B‐
CELL LYMPHOMA
Chair: Pier Luigi Zinzani, Bologna (Italy)
16:00 ‐17:30 Channel 4 Bayer
THE EVOLVING TREATMENT LANDSCAPE AND EMERGING NOVEL THERAPIES IN
INDOLENT NON‐HODGKIN'S LYMPHOMA (iNHL)
Chair: Martin Dreyling, Munich (Germany)
(Continues)
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13
(Continued)
Friday, June 18, 2021
18:00 – 19:30 Channel 1 Bristol Myers Squibb
ADVANCEMENTS OF CAR T CELL THERAPIES IN B‐CELL MALIGNANCIES
Chair: David Maloney, Seattle WA (USA)
18:00 – 19:30 Channel 2 F. Hoffmann‐La Roche
UNLOCKING THE FUTURE: SEARCHING FOR A CURE IN DLBCL
Chair: Georg Hess, Mainz (Germany)
18:00 – 19:30 Channel 3 Lymphoma Hub
SEQUENCING OF THERAPIES IN HIGH‐RISK RELAPSED/REFRACTORY LYMPHOMA
AND CLL
Chair: Gilles Salles, New York, NY (USA)
18:00 – 19:30 Channel 2 Novartis
EXPERT PERSPECTIVES IN CAR‐T: IDENTIFICATION, REFERRAL AND MANAGEMENT
OF PATIENTS WITH LYMPHOMA
Chair: Anna Sureda, Barcelona (Spain)
14
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Received: 18 February 2021
DOI: 10.1002/hon.2857
SUPPLEMENT ARTICLE
Langerhans cell histiocytosis: Version 2021
Nitya Gulati
1,2
|Carl E. Allen
1,2
1
Texas Children's Hospital Cancer and
Hematology Center, Houston, Texas, USA
2
Department of Pediatrics, Baylor College of
Medicine, Houston, Texas, USA
Correspondence
Carl E. Allen, Texas Children's Hospital Cancer
and Hematology Center, Houston, TX, USA.
Email: ceallen@txch.org
Abstract
Children with Langerhnans cell histiocytosis (LCH) develop granulomatous lesions
with characteristic clonal CD207+dendritic cells that can arise as single lesions or
life‐threatening disseminated disease. Despite the wide range of clinical pre-
sentations, LCH lesions are histologically indistinguishable based on severity of
disease, and uncertain classification as an immune versus neoplastic disorder has
historically challenged the development of optimal clinical strategies for patients
with LCH. Recently, activating somatic mutations in MAPK pathway genes, most
notably BRAFV600E, have been discovered in almost all cases of LCH. Further, the
stage of myeloid differentiation in which the mutation arises defines the extent of
disease and risk of developing LCH‐associated neurodegeneration. MAPK activation
in LCH precursor cells drives myeloid differentiation, inhibits migration, and inhibits
apoptosis, resulting in accumulation of resilient pathologic dendritic cells that re-
cruit and activate T cells. Recurrent somatic mutations in MAPK pathway genes
have also been identified in related histiocytic disorders: juvenile xanthogranuloma,
Erdheim–Chester disease, and Rosai–Dorfman disease. New insights into patho-
genesis support reclassification of these conditions as a myeloid neoplastic disor-
ders. Continued research will uncover opportunities to identify novel targets and
inform personalized therapeutic strategies based on cell of origin, somatic mutation,
inherited risk factors, and residual disease.
KEYWORDS
Erdheim–Chester disease, histiocytic disorder, juvenile xanthogranuloma, Langerhans cell
histiocytosis, Rosai–Dorfman disease
1
|
INTRODUCTION
Histiocytic disorders comprise a heterogeneous group of hematologic
and immunologic conditions historically classified based on histologic
similarities to cells of the mononuclear phagocyte system.
1
However,
with the rapidly increasing understanding of mechanisms of patho-
genesis and ontogeny, a revised classification is proposed that in-
cludes cellular origins, tissue distribution, and molecular lesions along
with histologic features (Tables 1and 2).
2
Langerhans cell histiocy-
tosis (LCH), the most common histiocytic disorder in children, is the
focus of this article. We will also briefly describe feature‐related
disorders: juvenile xanthogranuloma (JXG), Erdheim–Chester
disease (ECD), and sinus histiocytosis with massive lymphadenopathy
(SHML), also called Rosai–Dorfman disease (RDD).
2
|
LANGERHANS CELL HISTIOCYTOSIS
2.1
|
Pathophysiology
LCH has captured the attention of physicians and scientists for
more than 100 years. Clinical cases initially recognized in the early
1900s in children with unusual constellations of bone and pituitary
lesions (Hand–Schüller–Christian disease), aggressive disseminated
Hematological Oncology. 2021;39(S1):15–23. wileyonlinelibrary.com/journal/hon © 2021 John Wiley & Sons Ltd.
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15
disease (Letterer–Siwe disease), or isolated or multifocal bone le-
sions (eosinophilic granuloma). Pathologists in the 1950s noted
histologic similarity of biopsies from patients with these conditions
and proposed a unifying hypothesis that these clinically distinct
syndromes represent a common pathological entity, “Histiocytosis
X”. Subsequently, Nezelof and colleagues identified Birbeck gran-
ules’ pathologic histiocytes of LCH lesions (Figure 1), a feature at
that time was thought to be shared only with epidermal Langer-
hans cells.
LCH lesions are granulomatous lesions consisting of pathologic
“Langerhans cells” (LCs), lymphocytes (primarily T‐cells), eosinophils,
and macrophages. Like physiologic epidermal LCs (eLC), LCH lesion
LCs express CD1a and CD207 (langerin) surface markers (Figure 1
and Table 3). Common features among LCH and epidermal LC sup-
ported hypotheses of LCH as a reactive immune disorder, neoplastic
disorder, or some combination of both (reviewed in Allen et al.
4
). In
the 1990s, studies of X‐inactivation hinted at the clonal nature of
LCH lesion LCs. In 2010, Rollins and colleagues made a breakthrough
discovery of recurrent somatic BRAFV600E mutations in over 50% of
LCH lesions.
5
Subsequently, alternative BRAF mutations (indels and
fusions) and mutations in MAP2K1 (encoding MEK1) were also been
described. Mutually exclusive somatic activating mutations in MAPK
pathway genes have now been identified in approximately 85% LCH
lesions (Figure 2).
6
As discussed above, shared histology between epidermal LC
and LCH lesion histiocytes prompted updated branding from
“Histiocytosis X” to “Langerhans cell histiocytosis”. However, gene
expression studies comparing LCH lesion CD207+cells to eLC
revealed LCH cells to be relatively less differentiated. Subse-
quently, high‐sensitivity BRAFV600E PCR assays identified the
mutation in hematopoietic stem cells from bone marrow aspirate
and myeloid precursors from peripheral blood of patients with
disseminated LCH. Notably, BRAFV600E was not identified in
peripheral blood mononuclear cells from patients with single
BRAFV600E+lesions. Enforced expression of BRAFV600E in
langerin +cells in mice resulted in the formation of some
limited LCH‐like lesions with minimal impact on overall health,
but enforced expression in CD11c +myeloid cells drove rapid
formation of severe lesions in bone marrow, lung, liver, and
spleen resembling high‐risk LCH. Pathologic MAPK activation in
LCH lesion cells results in up‐regulation of anti‐apoptotic pro-
gram (Bcl‐xL) and down‐regulation of CCR7, which renders the
cells trapped in lesions, unable to migrate to draining lymph
nodes.
7
Addressing the decade‐long debate of LCH pathogenesis
arising from immune dysregulation versus transformation of eLC,
findings over the past decade reframe LCH as a myeloid
neoplastic disorder arising from myeloid precursors.
4
Together,
observations in LCH patients and mouse experiments support a
model of "Misguided Myeloid Differentiation," where state of
differentiation of myeloid precursor in which activating MAPK
mutation arises determines the extent and severity of disease
(Figure 3).
8
TABLE 1Historical classification of histiocytic disorders
Dendritic cell related
Langerhans cell histiocytosis
Juvenile xanthogranuloma/Erdheim–Chester disease
Macrophage related
Hemophagocytic syndromes
Primary hemophagocytic lymphohistiocytosis
Secondary hemophagocytic syndromes
Rosai–Dorfman disease
Malignant diseases
Monocyte‐related leukemias
Extramedullary monocytic tumor (myeloid sarcoma)
Macrophage‐related histiocytic sarcoma
Dendritic cell malignancy (malignant histiocytosis)
Note: Adapted from Favara et al.
1
TABLE 2Proposed revised classification of histiocytocytic
disorders
L group LCH
Intermediate‐cell histiocytosis (ICH)
Erdheim–Chester disease (ECD)
Mixed LCH/ECD
C group Cutaneous non‐LCH
‐Xanthomatous granuloma (XG) family: includes JXG
‐Non‐XG family includes cutaneous RDD
Cutaneous non‐LCH with major systemic component
‐XG family: xanthoma disseminatum
‐Non‐XG: multicentric reticulohistiocytosis
R group Familial RDD
Sporadic RDD
‐Classic RDD
‐Extranodal RDD
‐RDD with neoplasia or immune disease
‐Unclassified
M group Primary malignant histiocytosis
Secondary malignant histiocytosis
H group Primary HLH
Secondary HLH (non‐Mendelian)
HLH of unknown/uncertain origin
Note: Adapted from Emile et al.
2
Abbreviations: ECD, Erdheim–Chester disease; HLH, hemophagocytic
lymphohistiocytosis; JXG, juvenile xanthogranuloma; LCH, Langerhans
cell histiocytosis; RDD, Rosai–Dorfman disease.
16
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GULATI AND ALLEN
FIGURE 1 Histologic features of Langerhans cell histiocytosis (LCH). Panel A shows typical LCH lesions with large cells, pale cytoplasm,
and reniform nuclei on hematoxylin and eosin staining (A1); CD207‐positive immunostaining (A2); VE1‐positive immunostaining for BRAF
V600E protein (A3); and Birbeck granules visualized with electron microscopy (A4). Panel B shows liver involvement, which is frequently
characterized by periportal infiltration by histiocytes (B1) and variable CD207‐positive staining (B2). Panel C shows biopsy specimens from a
patient with severe LCH‐associated neurodegeneration (LCH‐ND), characterized by perivascular VE1‐positive staining (C1), CD163‐positive
staining (C2), and a P2RY12 infiltrate with occasional P2RY12‐positive, tissue‐resident microglia (C3). Panel D shows histiocytic lesions that
are characteristic of both LCH and juvenile xanthogranuloma (JXG), with heterogeneous histologic features on hematoxylin and eosin staining
(D1), including distinct cell populations that are CD207‐positive (D2) and CD68‐positive (D3) (from NEJM, LCH, 379:856–868
3
; Copyright
©2018 Massachusetts Medical Society. Reprinted with permission). JXG, juvenile xanthogranuloma
GULATI AND ALLEN
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17
2.2
|
Epidemiology
The incidence of LCH is estimated to be approximately 5–10 cases
per million children per year and 1–2 cases per million adults per year
with male‐to‐female ratio 1.2:1. Registry studies report an increased
incidence in Hispanic populations and rare occurrence of LCH in
children with African ancestry.
9
Notably, a GWAS trio study that
identified an increased risk of LCH in patients with a germline SMAD6
variant, which is enriched in Hispanic populations.
10
2.3
|
Clinical presentation and diagnostic workup
LCH has a wide range of clinical manifestations that can be difficult to
recognize due to overlap with more common conditions (Figure 4).
However, once LCH is considered, diagnosis is fairly straightforward
with biopsy. A stepwise approach to diagnosis and staging is outlined
in Table 4. Characteristic presentations include lytic bone lesions
(∼80% of cases), rash (∼20%–40% of cases), soft tissue swelling
(often in proximity to bony lesions), external ear drainage, lymph
node or thymic enlargement, and gum hypertrophy with premature
eruption of teeth. More severe systemic involvement reflected by
cytopenias, heptasplenomegaly, and/or impaired liver function por-
tends a higher risk of morbidity and mortality.Based on the findings
from Histiocyte Society trials, LCH is clinically divided into “high risk”
(liver, spleen, and/or bone marrow involvement) and “low risk” (le-
sions anywhere else), reflecting relative risk of death.
11
The signifi-
cance of “risk sites” in adults remains uncertain.
12
Historical
nomenclature (e.g., Letterer–Siwe) has been replaced with a more
generalized attribution of “LCH” along with description of extent of
disease (e.g., low‐risk single system; low‐risk multisystem; high‐risk
multisystem).
Beyond risk attribution, some characteristic sites merit discus-
sion. Skin lesions in infants may represent isolated skin disease with
potential to spontaneously resolve or a component of more extensive
systemic disease requiring chemotherapy. Gastrointestinal tract
involvement is rare but can present with severe diarrhea, hema-
tochezia, malabsorption, and hypoproteinemia. Isolated pulmonary
involvement is more common in young adults with a history of
chronic smoking in the third or fourth decades of life, but is occa-
sionally seen in children and adolescents. Pulmonary involvement
may lead to a severe, chronic debilitating course and often presents
with spontaneous pneumothorax. Central diabetes insipidus (DI) af-
fects approximately 25% of patients, most commonly seen in children
with systemic disease and the orbit and skull involvement. Most
cases of DI present with initial systemic disease, but can also present
as isolated pituitary disease, or arise as a site of relapse. While
posterior pituitary involvement is more common, other endocrine
manifestations associated with LCH may include growth hormone
deficiency, adrenal insufficiency, hyperprolactinemia, or hypogonad-
ism caused by hypothalamic infiltration of the anterior pituitary
gland.
13
LCH‐associated neurodegeneration (LCH‐ND) is one of the most
severe complications of LCH. LCH‐ND may develop with the onset of
LCH or several years after the patient has completed therapy and is
presumed to be in remission. The presence of “central nervous sys-
tem (CNS)‐risk” bone lesions (orbit, mastoid, maxilla, temporal,
sphenoid, zygomatic, and clivus) or pituitary lesions at the time of
initial diagnosis is thought to increase the risk of developing LCH‐ND.
While the true risks of “CNS‐risk” require additional investigation,
current practice is generally to treat isolated CNS risk lesions with
systemic chemotherapy. BRAFV600E mutation is also associated with
increased risk of LCH‐ND. Patients with LCH‐ND typically present
with prolonged decline in cognitive abilities, worsening school per-
formance, and/or development of cerebellar symptoms. Character-
istic magnetic resonance imaging (MRI) findings include T2 hyper‐
intense diffuse or polymorphic lesions involving the white matter of
the cerebellum, pons, basal ganglia, and less often the cerebral
hemispheres (Figure 4).
14
The etiology of LCH‐ND remained uncer-
tain for years, with limited biopsy studies demonstrating lymphocytic
infiltration and activated microglia interpreted as a paraneoplastic or
autoimmune phenomenon. More recent studies demonstrate
microglia‐like mononuclear cells at sites of neurodegeneration with
BRAFV600E, supporting clonal origin with systemic LCH lesions
(Figure 1).
15
2.4
|
Therapy
2.4.1
|
Local LCH
Treatment options depend on the site and extent of the disease.
Isolated skin lesions sometimes resolve spontaneously, with topical
steroids, or with oral immune suppression (e.g., methotrexate or
hydroxyurea). Single bone lesions in readily accessible and non‐CNS‐
TABLE 3Histologic features of histiocytic disorders
LCH ECD/JXG RDD
HLA‐DR ++ − +
CD1a ++ − −
CD14 +/− ++ ++
CD68 +/− ++ ++
CD163 − + ++
CD 207 (Langerin) +++ − −
Factor XIIIa − ++ −
Fascin − ++ +
Birbeck granules + − −
Hemophagocytosis +/− − −
Emperiopolesis − − +
Note: Adapted from Jaffe.
3
Abbreviations: ECD, Erdheim–Chester disease; HLH, hemophagocytic
lymphohistiocytosis; JXG, juvenile xanthogranuloma; LCH, Langerhans
cell histiocytosis; RDD, Rosai–Dorfman disease.
18
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GULATI AND ALLEN
risks sites may be treated with curettage and/or steroid injection.
Notably, unlike other pediatric “cancer”, LCH does not require
complete excision with “clean” margins—in fact, extensive bone
resection can impair bone remodeling.
2.4.2
|
Frontline therapy
Multiple lesions indicate potential for remote clonal progenitors.
Patients with multiple lesions therefore typically require systemic
chemotherapy. The current standard of care for initial therapy is
vinblastine/prednisone for 1 year (with mercaptopurine added for
high‐risk LCH), based on the Histiocyte Society LCH‐III trial. LCH‐
III study demonstrated higher rates of progression‐free survival
(PFS) in patients treated for 1 year versus 6 months (5‐year PFS
54% vs. 37%; p=0.03) and no benefit of adding methotrexate
for patients with high‐risk LCH.
16
Notably, fewer than 50% of
patients with high‐risk LCH were cured with vinblastine/predni-
sone. While vinblastine/prednisone may be the current standard,
improved strategies are clearly needed. The Histiocyte Society is
FIGURE 2 MAPK pathway mutations in histiocytic disorders. (A) (left) Schematic of MAPK pathway. Under physiologic conditions, the
growth factor (gray box) engages the tyrosine kinase receptor that transduces the signal to the nucleus. (right) Activating mutations (such as
BRAF‐V600E) drive constitutive ERK activation. In the case of LCH, this drives the expression of anti‐apoptosis BCL2L1 (BCL‐xL) and inhibits
CCR7. (B) Stacked bar graphs represent percentages of MAPK pathway mutations in each histiocytic histologic subtype.
GULATI AND ALLEN
-
19
currently testing the impact of further treatment prolongation (2
vs. 1 year with vinblastine/prednisone/(mercaptopurine) for
frontline therapy (NCT02205762). Another phase 3 trial is
currently randomizing 1 year of vinblastine/prednisone/mercapto-
purine versus 1 year of cytarabine monotherapy for frontline LCH
(NCT02670707).
FIGURE 4 Clinical presentations of Langerhans cell histiocytosis (LCH). Positron‐emission tomographic (PET) images show a single
bone lesion involving the humerus (Panel A, arrow); low‐risk lesions involving the orbit, lymph nodes, bone (multifocal lesion), and thymus
(Panel B); and high‐risk lesions involving the liver, spleen, and bone marrow (Panel C). Other classic presentations include a lytic bone
lesion (Panel D, arrow), cystic lung lesions (Panel E), and various skin lesions (Panels F through I). Examples of LCH lesions involving the
skull and brain include multifocal skull lesions (Panel J, arrow), an orbital lesion (Panel K, arrow), a pituitary lesion (Panel L, arrow), and
LCH‐associated neurodegeneration (Panel M, arrow). (from NEJM, LCH, 379:856–8683; Copyright ©2018 Massachusetts Medical
Society. Reprinted with permission)
FIGURE 3 Ontogeny of tissue “histiocytes.” Tissue macrophages and dendritic cells seed tissues at various stages of development.
Microglia, Küpffer cells, and Langerhans cells (LCs) arise from yolk‐sac‐derived progenitors, followed by fetal liver, then adult hematopoiesis.
Note. Langerhans cells may be generated from adult HSC monocyte‐derived LCs following inflammation or tissue damage. The arrows denotes
the sites of LCH lesions
20
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GULATI AND ALLEN
2.4.3
|
Salvage therapy
Nucleoside analogs
Optimal approaches for patients who have relapsed or refractory
LCH following frontline therapy have not been established. In two
phase 2 studies, high‐dose cytarabine/cladribine was effective, but
associated with significant treatment‐related morbidity and mortal-
ity. By comparison, lower‐dose cladribine monotherapy induced high
response rates, but only 3% of patients were cured after 6 months of
therapy. Institutional series support the potential efficacy of
intermediate‐dose cytarabine or clofarabine monotherapy for
relapsed and refractory LCH. While nucleoside analogs are prom-
ising, prospective trials are needed to determine optimal agent(s),
dose, and duration. Allogeneic hematopoietic cell may also be cura-
tive, but associated with >25% mortality (reviewed in Rodriguez‐
Galindo and Allen
13
).
Targeted therapy
New concepts of LCH pathogenesis offer an opportunity to move the
treatment for LCH beyond empiricism to rational strategies. Early
adult trials have reported extremely high response rates to MAPK
pathway‐directed targeted therapy with BRAFV600E or MEK inhi-
bition for LCH and ECD.
17,18
Retrospective series report similar
findings for children with LCH. However, despite high response rates,
MAPK pathway inhibition does not appear to be curative.
19,20
Additionally, duration of therapy, durability of response, and poten-
tial for re‐response after stopping the medication, and patterns of
response/resistance are unknown. In LCH patients treated with
MAPK pathway inhibitors, PBMCs with BRAF‐V600E (presumed
precursors) do not consistently clear from circulation, even in pa-
tients with complete clinical responses, and patient almost univer-
sally relapsed with cessation of therapy.
19,20
Thus, there is an urgent
need to improve therapeutic strategies (e.g., MAPK inhibitors with
TABLE 4Clinical evaluations for newly diagnosed LCH
Initial evaluation
�History, physical examination
�Laboratory studies
a. Complete blood count
b. Serum chemistry
c. Liver function test
d. Sedimentation rate (ESR)
e. Lactate dehydrogenase (LDH)
f. Serum ferritin
g. Immunoglobulin profile
h. PT/INR, aPTT (with evidence of liver dysfunction)
�Imaging
a. Skeletal survey with two views of chest and four views of the skull (if PET/CT not obtained).
Confirmation of LCH and extent of disease evaluation
�PET/CT
�Diagnostic biopsy‐excisional biopsy is preferred. Curettage of bone lesions is optimal and complete excision is not required. The presence of
abnormal clusters of CD1a+/CD207+histiocytes are diagnostic (Note: normal skin and lymph node biopsies may include scattered physiologic CD207+
Langerhans cells). CD163, fascin, and factor XII help identify mixed histiocytic lesions (such as JXG/LCH, ECD/LCH)
Additional studies(based on lab and/or clinical features)
�All patients <2 years of age, any patients with cytopenias, liver and spleen involvement
a. Bilateral bone marrow aspirate and biopsy
�Any skull lesions (based on physical exam or lytic lesions on skull x‐rays)—CT skull/maxillofacial scans
�CNS‐risk lesions
a. MRI brain with and without contrast for patients with CNS‐risk lesions
b. For auditory canal or temporal bone involvement, also perform a hearing evaluation
c. For clinical suspicion of DI, pituitary dysfunction, or thickened pituitary stalk on MRI brain–urine specific gravity, urine and serum osmolality/
water deprivation test. (Note: If there is an isolated DI and thickened pituitary stalk without any other features suggestive of LCH, perform diagnostic LP
for cytology and AFP/B‐HCG to rule out germ cell tumor).
d. Other endocrine evaluation as indicated
e. Baseline neurocognitive evaluation for patients with DI or evidence of LCH‐ND
�Spinal cord or vertebral involvement‐MRI spine with and without contrast
�Pulmonary involvement‐CT chest (chest x‐rays and PET/CT may miss small pulmonary nodules, cysts, or thymic involvement).
�Elevated transaminases, elevated direct bilirubin or decreased albumin‐abdominal US or MRI
�History of malabsorption or hypoalbuminemia‐lower GI endoscopy
Abbreviations: DI, diabetes insipidus; ECD, Erdheim–Chester disease; HLH, hemophagocytic lymphohistiocytosis; JXG, juvenile xanthogranuloma; LCH,
Langerhans cell histiocytosis; LCH‐NH, LCH‐associated neurodegeneration; RDD, Rosai–Dorfman disease.
GULATI AND ALLEN
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21
chemotherapy or anti‐apoptotic agents or epigenetic modifiers) to
safely cure patients with LCH and related disorders.
2.5
|
Adult LCH
The natural history of LCH in adults is understudied. Except for the
predominance of lung disease, LCH appears to involve the same
potential organ distribution as seen in children, though the incidence
may be different. For example, pulmonary LCH usually occurs as a
single‐system disease in patients, 90% of the cases in adults who are
heavy chronic smokers. Other differences include a higher incidence
of oral and genital mucosa involvement in adults. Whole exome
sequencing studies demonstrate higher somatic mutation burden in
adult versus pediatric LCH (where median exome mutation is ∼1).
When LCH arises de novo in adults, it may reflect acquisition of
mutation(s) through clonal hematopoiesis, reflected by mixed‐
phenotype myeloproliferative neoplastic disorders in some patients.
For adults with single LCH lesions, management strategies
similar to the pediatric population include curettage (clean margins
are not required) with or without intralesional corticosteroids for
single‐bone lesions. However, there is no standard of care for the
management of multisystem disease. Vinblastine/prednisone may
have higher toxicity in adult patients, favoring alternatives such as
cytarabine monotherapy. Other options include cladribine, clofar-
abine, hydroxyurea, methotrexate, 6MP, and MAPK pathway
inhibitors.
12
2.6
|
Non‐Langerhans cell histiocytic disorders
Juvenile xanthogranuloma (JXG) is a histiocytic disorder that
shares many features with macrophage histology, and is histo-
logically indistinguishable from ECD (Table 3). It most commonly
affects infants and young children with a slight male predomi-
nance and presents as one or more “fleshy skin nodules.”
However, in some patients, it may be systemic (<5% pediatric
cases), involving multiple organs including deeper soft tissue,
CNS, bone, lung, liver, spleen, pancreas, adrenal glands, in-
testines, kidneys, lymph nodes, bone marrow, orbit, and heart.
The etiology and basis for prevalence in children are not well
defined. An association between JXG and neurofibromatosis
(types 1 and 2) and juvenile myelomonocytic leukemia and other
molecular alterations such as CSF1R,KRAS,NRAS, and MAP2K1
(rarely BRAFV600E) implicates constitutive MAPK activation in
pathogenesis (Figure 2).
6
Erdheim–Chester disease (ECD) typically arises in patients between
the ages of 40 and 70, with a male predominance. Typical pre-
sentations include xanthelasma on the upper eyelids, skin rash, and
bilateral lower limb bone pain. Consensus diagnostic criteria for ECD
require the presence of (1) foamy CD68+/CD1a−histiocytes
(Table 3), often with admixed inflammation and fibrosis, and
(2) radiographic findings of bilateral and symmetric abnormalities in
the diaphyseal and metaphyseal regions of the long bones of the legs.
More severe manifestations can include cardiopulmonary insuffi-
ciency, renal failure due to retroperitoneal/perinephric infiltration, or
CNS symptoms such as cerebellar signs, DI, or cognitive dysfunction.
Like LCH, ECD is characterized by activating somatic MAPK pathway
gene mutations (BRAFV600E being the most common in approxi-
mately 50% of patients) (Figure 2). ECD historically carried a dismal
prognosis that has been significantly improved with MAPK inhibitors.
In 2017 vemurafenib was approved for BRAFV600E +ECD; and
MEK inhibition has also been reported with high response rates
(reviewed in Goyal et al.
21
).
RDD or SHML likely represents a variety of conditions that share
pathologic CD68+/CD1a−cells with emperipolesis (trafficking of
viable lymphocytes through histiocytes) (Table 3). It can occur either
as an isolated disorder or in conjunction with another autoimmune,
malignant, or hereditary disease. Chronic, painless, massive cervical
lymphadenopathy is the most common presentation. Other nodal
areas and extranodal sites (such as skin, upper respiratory mucosa,
ocular structures, bones, and CNS) may also be involved. Treatment
is variable and depends on the number of involved sites and can
range from observation to systemic chemotherapy. MAPK mutations
have been reported in RDD lesions, but less reliably than the other
histiocytic disorders discussed above (Figure 2) (reviewed in Abla
et al.
22
).
3
|
CONCLUSIONS
Clinical advances for patients with LCH and related disorders
have historically been stalled by undefined mechanisms of path-
ogenesis. However, accelerated advances over the past decade
have defined LCH as an inflammatory myeloid neoplastic disorder
with extent of disease determined by the cell of origin in which
activating MAPK somatic mutations arise. The challenge we now
face is how to translate biological discovery into improved out-
comes for children and adults with histiocytic disorders.
Continued research on LCH, JXG, ECD, and RDD will uncover
opportunities to identify novel targets and inform personalized
therapeutic strategies based on cell of origin, somatic mutation,
and inherited risk factors.
ACKNOWLEDGMENT
Dr. Allen receives support from the HistioCure Foundation, St. Bal-
drick's Foundation (Innovation Grant, Consortium Grant), the Moves
for Miles Childhood Cancer Foundation, and the Leukemia and
Lymphoma Society (Translational Research Program).
CONFLICT OF INTEREST
The authors have no conflicts to report with respect to this
manuscript.
ORCID
Carl E. Allen https://orcid.org/0000-0002-6625-739X
22
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GULATI AND ALLEN
REFERENCES
1. Favara BE, Feller AC, Pauli M, et al. Contemporary classification of
histiocytic disorders. Med Pediatr Oncol. 1997;29:157‐166.
2. Emile JF, Abla O, Fraitag S, et al. Revised classification of histiocy-
toses and neoplasms of the macrophage‐dendritic cell lineages.
Blood. 2016;27:2672‐2681.
3. Jaffe R. The diagnostic histopathology of Langerhans cell histiocy-
tosis. In: Weitzman S, Egeler RM, eds. Histiocytic Disorders of Children
and Adults. Basic Science Clinical Features, and Therapy. Cambridge
University Press; 2005:14‐39.
4. Allen CE, Merad M, McClain KL. Langerhans‐cell histiocytosis. N Engl
J Med. 2018;379:856‐868.
5. Badalian‐Very G, Vergilio J‐A, Degar BA, et al. Recurrent BRAF
mutations in Langerhans cell histiocytosis. Blood. 2010;116:
1919‐1923.
6. Durham BH, Lopez Rodrigo E, Picarsic J, et al. Activating mutations
in CSF1R and additional receptor tyrosine kinases in histiocytic
neoplasms. Nat Med. 2019;25:1839‐1842.
7. Hogstad B, Berres ML, Chakraborty R, et al. RAF/MEK/extracellular
signal‐related kinase pathway suppresses dendritic cell migration
and traps dendritic cells in Langerhans cell histiocytosis lesions. J Exp
Med. 2018;215:319‐336.
8. Berres M‐L, Lim KPH, Peters T, et al. BRAF‐V600E expression in
precursor versus differentiated dendritic cells defines clinically
distinct LCH risk groups. J Exp Med. 2014;211:669‐683.
9. Ribeiro KB, Degar B, Antoneli CBG, Rollins B, Rodriguez‐Galindo C.
Ethnicity, race, and socioeconomic status influence incidence of
Langerhans cell histiocytosis. Pediatr Blood Cancer. 2015;62:
982‐987.
10. Peckham‐Gregory EC, Chakraborty R, Scheurer ME, et al. A
genome‐wide association study of LCH identifies a variant in
SMAD6 associated with susceptibility. Blood. 2017;130:2229‐2232.
11. Gadner H, Grois N, Pötschger U, et al. Improved outcome in multi-
system Langerhans cell histiocytosis is associated with therapy
intensification. Blood. 2008;111:2556‐2562.
12. Girschikofsky M, Arico M, Castillo D, et al. Management of adult
patients with Langerhans cell histiocytosis: recommendations from
an expert panel on behalf of Euro‐Histio‐Net. Orphanet J Rare Dis.
2013;8:72.
13. Rodriguez‐Galindo C, Allen CE. Langerhans cell histiocytosis. Blood.
2020;135:1319‐1331.
14. Yeh EA, Greenberg J, Abla O, et al. Evaluation and treatment of
Langerhans cell histiocytosis patients with central nervous system
abnormalities: current views and new vistas. Pediatr Blood Cancer.
2017;65.
15. McClain KL, Picarsic J, Chakraborty R, et al. CNS Langerhans cell
histiocytosis: common hematopoietic origin for LCH‐associated
neurodegeneration and mass lesions. Cancer. 2018;124.
16. Gadner H, Minkov M, Grois N, et al. Therapy prolongation improves
outcome in multi‐system Langerhans cell histiocytosis. Blood.
2013;121.
17. Diamond EL, Subbiah V, Lockhart AC, et al. Vemurafenib for BRAF
V600‐Mutant Erdheim‐Chester disease and Langerhans cell histio-
cytosis: analysis of data from the histology‐independent, phase 2,
Open‐label VE‐BASKET study. JAMA Oncol 2017;4(3).
18. Haroche J, Cohen‐Aubart F, Emile J‐F, et al. Dramatic efficacy of
vemurafenib in both multisystemic and refractory Erdheim‐Chester
disease and Langerhans cell histiocytosis harboring the BRAF V600E
mutation. Blood. 2013;121:1495‐1500.
19. Donadieu J, Larabi IA, Tardieu M, et al. Vemurafenib for refractory
multisystem Langerhans cell histiocytosis in children: an interna-
tional observational study. J Clin Oncol. 2019;JCO1900456.
20. Eckstein OS, Visser J, Rodriguez‐Galindo C, Allen CE. Clinical re-
sponses and persistent BRAFV600E+blood cells in children with
LCH treated with MAPK pathway inhibition. Blood. 2019;133(15):
1691‐1694.
21. Goyal G, Heaney ML, Collin M, et al. Erdheim‐Chester disease:
consensus recommendations for evaluation, diagnosis, and treat-
ment in the molecular era. Blood. 2020;135:1929‐1945.
22. Abla O, Jacobsen E, Picarsic J, et al. Consensus recommendations for
the diagnosis and clinical management of Rosai‐Dorfman‐
Destombes disease. Blood. 2018;131:2877‐2890.
How to cite this article: Gulati N, Allen CE. Langerhans cell
histiocytosis: Version 2021. Hematological Oncology.
2021;39(S1):15–23. https://doi.org/10.1002/hon.2857
GULATI AND ALLEN
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23
Received: 17 February 2021
DOI: 10.1002/hon.2847
SUPPLEMENT ARTICLE
Molecular classification of aggressive lymphomas—past,
present, future
Kirsty Wienand |Björn Chapuy
Department of Hematology and Medical
Oncology, University Medical Center
Göttingen, Göttingen, Germany
Correspondence
Björn Chapuy, Department of Hematology
and Medical Oncology,University Medical
Center Göttingen Robert‐Koch Str. 40, 37075
Göttingen, Germany.
Email: bjoern.chapuy@med.unigoettingen.de
Abstract
Aggressive large B‐cell lymphomas (LBCLs) represent a frequent but clinically and
molecularly heterogeneous group of tumors. Technological advances over the last
decades prompted the development of different classification schemas to either
sharpen diagnoses, dissect molecular heterogeneity, predict outcome, or identify
rational treatment targets. Despite increased diagnostic precision and a noticeably
improved molecular understanding of these lymphomas, clinical perspectives of pa-
tients largely remain unchanged. Recently, finished comprehensive genomic studies
discovered genetically defined LBCL subtypes that predict outcome, provide insight
into lymphomagenesis, and suggest rational therapies with the hope of generating
patient‐tailored treatments with increased perspective for patients in greatest need.
Current and future efforts integrate multiomics studies and/or leverage single‐cell
technologies and will provide us with an even more fine‐grained picture of LBCL
biology. Here, we highlight examples of how high‐throughput technologies aided in a
better molecular understanding of LBCLs and provide examples of how to select
rationally designed targeted treatment approaches that might personalize LBCL
treatment and eventually improve patients' perspective in the near future.
KEYWORDS
biomarker, diffuse large B‐cell lymphoma, high‐grade B‐cell lymphoma, immune escape,
molecular classification, precision medicine, primary central nervous system, primary
mediastinal large B‐cell lymphoma, primary testicular lymphoma
1
|
CAPTURING MOLECULAR HETEROGENEITY
OF AGGRESSIVE B‐CELL LYMPHOMA
Large B‐cell lymphomas (LBCLs) represents a clinically and molecu-
larly heterogeneous group of aggressive non‐Hodgkin lymphomas
that largely arise from antigen exposed B cells and include primary
mediastinal large B‐cell lymphoma (PMBL), primary central nervous
system lymphoma (PCNSL), primary testicular lymphoma (PTL), and
diffuse large B‐cell lymphoma (DLBCL).
1
Of those, DLBCL often in-
volves multiple nodal and extranodal sites, while PMBL, PCNSL, and
PTL present as localized masses in extranodal sites (Figure 1). Over
the last decade, the molecular heterogeneity of these tumors was
captured in various classification schemes that (i) improved the ac-
curacy of diagnosis; (ii) identified relevant molecular subtypes; (iii)
allowed the development of prognostic and/or predictive markers;
and (iv) provided insight into the associated biology.
Technological advances in recent years have the allowed
detection and prioritization of all genetic alterations types—
recurrent mutations, somatic copy number alterations (SCNAs) and
structural variants (SVs)—followed by integration and assessment of
This is an open access article under the terms of the Creative Commons Attribution‐NonCommercial‐NoDerivs License, which permits use and distribution in any
medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.
© 2021 The Authors. Hematological Oncology published by John Wiley & Sons Ltd.
24
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Hematological Oncology. 2021;39(S1):24–30. wileyonlinelibrary.com/journal/hon
their temporal ordering and associated transcriptional profiles.
These comprehensive genomic profiles at base‐pair resolution of
hundreds of patients diagnosed with primary LBCL has captured the
complex intrinsic genetic heterogeneity of these lymphomas, high-
lighted similarities and differences across entities, identified previ-
ously not defined molecular subtypes, provided better insight into
the underlying biology, led to the discovery of rational‐targeted
therapies and might be used to stratify patients for treatments
(Figure 1).
2
|
PRIMARY MEDIASTINAL LARGE B‐CELL
LYMPHOMAS
PMBL is a rare LBCL that predominantly occurs in young women and
was initially categorized as a morphological subtype of DLBCL.
1
Transcriptional profiling of PMBL revealed reduced expression of
B‐cell receptor (BCR) signaling components, including surface
immunoglobulin, and constitutive activation of Janus kinase (JAK)/
signal transducer and activator of transcription (STAT) and nuclear
factor‐κB (NF‐κB) signaling cascades, molecular features reminiscent
of classical Hodgkin lymphoma (cHL) (Figure 1).
2–4
The shared clin-
ical, pathomorphological, and molecular features of PMBL and cHL,
and differences between PMBL and DLBCL led to the recognition of
PMBL as a distinct lymphoma entity.
1
Subsequent studies have defined genetic mechanisms underly-
ing the activation of NF‐κB and JAK/STAT signaling pathways,
including the identification of the recurrently amplified region on
9p/9p24.1, which includes JAK2 and increases JAK/STAT signaling
in PMBL.
5–8
Interestingly, the 9p24.1 amplified region also affected
the PD‐1 ligands, namely PD‐L1 (CD274) and PD‐L2 (PDCD1LG2),
providing a genetic mechanism of immune escape in PMBL.
4,5,8
Notably, the coamplification of PD‐L1/PD‐L2 and JAK2 increases the
expression of the PD‐1 ligands both directly, by increasing their
copy number, and indirectly, increases the ligands' expression via
JAK/STAT signaling and thereby result in an effective immune
escape.
5,9
SVs deregulating PD‐L1 and PD‐L2 by translocation,
inversion, or deletion of the 30‐untranslated region of PD‐L1 have
also been reported in PMBL.
10
The success of immune checkpoint
blockade with PD‐1 blocking agents in cHL
11–14
and these striking
genetic similarities between PMBL and cHL prompted the clinical
evaluation of PD‐1 blockade in PMBL. The high response rate of
single PD‐1 blockade with pembrolizumab in relapsed/refractory
PMBL led to rapid FDA approval in 2018 and underscored the
importance of characterizing targetable genetic vulnerabilities in
this disease and related lymphoma.
15,16
Interestingly not all patients
with genetic bases of PD‐1 deregulation responded to PD‐1
blockade
15,16
which resulted in additional clinical trials that com-
bined PD‐1 blockade with other rational targets, such as the anti‐
CD30 antibody–drug conjugate, brentuximab vedotin, with prom-
ising responses and duration.
15
The clinical heterogeneity in responses to PD‐1 blockade of
PMBL warranted further molecular understanding and resulted in
comprehensive genomic studies that captured somatic mutations,
SCNAs and SVs and prioritized candidate cancer genes (CCGs).
17,18
These studies highlighted that CCGs can be perturbed by more
than one genetic mechanism and that multiple genetic alterations
converge on specific signaling pathways, including the NF‐κB and
JAK/STAT signaling pathways (Figure 1).
17,18
One of these studies
highlighted previously unappreciated aspects of the PMBL genetic
signature that was shared with those in cHL, and could be asso-
ciated with an increased response rate to PD‐1‐blockade, including
frequent genetic alterations affecting the ligands of the PD‐1 (PD‐
L1/PD‐L2) with increased PD‐1 expression, and a relatively high
mutational burden, compared to that in other lymphoid and solid
cancers.
17,19
Additionally, both PMBLs and cHLs exhibit microsat-
ellite instability and APOBEC mutational signatures that have been
associated with a more favorable response to PD‐1 blockade.
20,21
On the other side, PMBLs, like cHLs, exhibited multiple genetic
bases of perturbed major histocompatibility complex (MHC) class I
expression and less frequently decreased MHC class II expression
that also impacted the cellular composition of the tumor micro-
environment
17
and likely could be associated with reduced
response to PD‐1 blockade. Importantly, these studies provided a
genomic framework to comprehensively assess molecular mecha-
nisms of response and resistance to PD‐1 blockade in subsequent
studies and provide the basis for additional rational combination
therapies.
FIGURE 1 Aggressive lymphoma is classified into different entities and subtypes based on morphology/clinically, transcriptomic,
cytogenetic, and genomic features
WIENAND AND CHAPUY
-
25
3
|
PRIMARY CENTRAL NERVOUS SYSTEM
LYMPHOMA AND PRIMARY TESTICULAR
LYMPHOMA
PCNSL and PTL, that both arise in sites previously described as im-
mune sanctuaries, are primary extranodal LBCLs with inferior re-
sponses to current empiric treatment regimens.
22,23
Prior studies had
focused on individual epigenetic or genetic features and transcrip-
tional profiling had suggested that PCNSL/PTL share similarities to
the activated B‐cell (ABC) subtype of systemic DLBCL (Figure 1).
24
To gain insight into potential actionable genetic alterations a
comprehensive study characterized the genomic landscape of PCNSL
and PTL and compared the derived genetic alterations to those in
DLBCL and PMBL. That study identified unique combinations of ge-
netic alterations (i.e., genetic signatures) for discrete LBCL subtypes
and putative bases for targeted therapy.
8,25
For instance, like PMBL,
PCNSL, and PTL exhibited frequent 9p24.1/PD‐L1/PD‐L2 genetic
alteration,
8
providing a genetic basis of affecting the immune
checkpoint pathway (Figure 1). Encouraged by the high response
rates in lymphomas with genetic bases of PD‐1 deregulation (cHL and
PMBL), checkpoint inhibition with PD‐1 blocking antibodies is
currently being tested clinically.
26
PCNSL and PTL, like DLBCL,
frequently exhibited genomic instability, but the molecular mecha-
nisms operating in PTL and PCNSL are distinct from DLBCL and
largely caused by high‐level copy losses of the tumor‐suppressor
CDKN2A,
8
while in DLBCL several monoallelic alterations in p53
modifiers were observed.
27
Additionally, PCNSL and PTL harbored
frequent MYD88
L265P
mutations and NFKBIZ copy gains leading to
near‐uniform oncogenic Toll‐like receptor (TLR) activation.
8
Notably,
most of the PCNSLs had mutations in the proximal BCR‐associated
gene, CD79B
8,25
similarly to a subset of ABC–DLBCLs (Figure 1).
28–30
This mutational pattern is reminiscent of a discrete molecular sub-
type of DLBCL that is depending on oncogenic TLR signaling
involving an endosomal multiprotein super complex (i.e., My‐T‐BCR
complex).
29–31
The importance of this oncogenic pathway in PCNSL is
further substantiated by recent insights that highlighted the role of
autoantigens and associated chronic BCR stimulation for the brain
tropism of malignant PCNSL B cells.
32,33
Consistently, the clinical
evaluation of targeted inhibitors against the BCR‐and TLR‐signaling
pathways, including BTK inhibitors, such as ibrutinib alone or in
conjunction with intensive chemoimmunotherapy,
34
or lenalidomide
and derivatives are under clinical evaluation.
35
4
|
HIGH GRADE B‐CELL LYMPHOMA WITH MYC
TRANSLOCATION AND/OR BCL2 TRANSLOCATION
AND/OR BCL6 TRANSLOCATION
In 2016, the World Health Organization (WHO) has recognized a
rare but high‐grade B‐cell lymphoma with MYC and BCL2 and/or
BCL6 rearrangements to be included in a single category (high grade
B‐cell lymphoma), also known under the prior clinical acronym
“double hit”/ “triple hit” lymphoma, and suggested a provisional entity
(Figure 1).
1,36
According to WHO guidelines
1,36
, all aggressive B‐cell
tumors with a germinal center B‐cell (GCB) phenotype or high‐grade
morphological features or to cases with more than 40% MYC‐
expressing cells should be tested by Fluorescence in situ hybridiza-
tion (FISH) for translocations in MYC,BCL2, and BCL6 and in case of
double positivity grouped in this categories. Due to different tech-
niques, cut offs and less standardization these tumors are less well
defined. Currently, this is an active area of research in which several
groups attempt to define standards and capture some of the biology
by gene‐expression‐based or genetic platforms. However, while
initial reports suggested an dismal clinical outcome,
37–39
more recent
reports suggests that with more frequent testing the outcome be-
comes less dismal.
29,40,41
A recent multi‐institutional intranational
retrospective study reanalyzed all patients with this genotype using
FISH and highlighted that the negative prognostic impact is only
present when MYC was juxtaposed to the IgH enhancer.
41
This data
suggests that in the initial reports were probably based on some
selection bias and that a comprehensive characterization of these
lymphomas is still needed as it is likely that this category itself re-
flects a heterogenous group of tumors.
5
|
DIFFUSE LARGE B‐CELL LYMPHOMA
DLBCL is the most common aggressive LBCL accounting for up to
35% of all lymph node cancers. Although the majority of patients with
DLBCL are curable with combination immunochemotherapy con-
sisting of rituximab, cyclophosphamide, doxorubicin, vincristine, and
prednisolone (R‐CHOP), a substantial fraction of patients develop
recurrent or progressive disease that is often fatal. This clinical
heterogeneity had inspired decades of researchers to develop clinical
and/or molecular classifiers capturing the biology, of which several
provide some prognostic guidance and others help to dissect the
molecular underpinnings of the disease. Some of the new next gen-
eration sequencing (NGS)‐based classifications might even pave the
way to become the first molecular predictive markers in this disease.
5.1
|
Clinical heterogeneity
Clinically, the most widely used risk model is the international
prognostic index (IPI), that has been established in the last century,
42
and with minimal changes, that is until today the most robust clinical
model used in daily routine.
43
Key criticism of the IPI is the missing
link to molecular features that might be amenable to targeted
therapy.
5.1.1
|
Morphological heterogeneity
Initial attempts to leverage morphological subtypes and explore their
power for classification is not extensively used with the exception of
recognizing T‐cell/histiocyte‐rich large B‐cell lymphoma (THRBCL).
26
-
WIENAND AND CHAPUY
THRBCL is a morphological subtype, in which the rare malignant
DLBCL cell is surrounded by a brisk but ineffective inflammatory
background (Figure 1).
1
For that reason, earlier studies explored
the genetic similarities between TCRLBCL and nodular lymphocyte
predominant Hodgkin lymphoma.
44
Recent works further support a
genetic relationship to cHL and PMBL, as TCRLBCL also exhibits
frequent PD‐1 ligand expression and a genetic bases of PD‐1‐medi-
ated immune escape.
45,46
5.1.2
|
Transcriptional heterogeneity
Besides recognized morphological subtypes,
1
the heterogeneity of
DLBCL is also partially captured in transcriptionally defined sub-
types that provide insights into disease pathogenesis and candidate
treatment targets.
28,47–51
The cell‐of‐origin (COO) classification
identifies ABC‐and GCB‐type DLBCLs,
47,52
based on whole tran-
scriptome gene expression profiling and similarities to normal B‐
cell counterparts (Figure 1).
53
An alternative transcriptional clas-
sification subdivides primary DLBCLs into BCR signaling, oxidative
phosphorylation, and host response DLBCLs based on unsuper-
vised consensus clustering solely in the space of DLBCLs without
comparison to normal tissue (consensus cluster classification;
Figure 1).
48
Also this transcriptional classification prompted in
subsequent studies the discovery of BCR and metabolic de-
pendencies of the respective DLBCL subsets.
50,51,54
The widely
used ABC and GCB distinction had also provided insights into the
biological differences with increase baseline NF‐κB signaling and
an differentiation block towards plasma cells in ABC‐type DLBCLs
and an epigenetic locking into the germinal center program in GCB
DLBCLs (for detailed biology reviews on ABC/GCBs see Refer-
ences 52 and 56). In particular, driven by outcome differences
between the two transcriptional phenotypes in some studies (ABC,
inferior clinical outcome), a plethora of parsimonious assays
including immunohistochemistry (IHC),
55
digital gene expression
such as nanostring‐based assays
56
or NGS approaches have been
developed. Despite numerous issues regarding accuracy and
reproducibility of IHC‐based assays, it is extensively used in
practice and biomarker‐driven studies. Thus far, patient stratifica-
tion for treatment based on transcriptional subtypes either by IHC
or gene expression‐based stratifications have been unsuccessful.
Moreover, although patients with ABC DLBCLs are reported to
have less favorable responses to standard therapy than those with
GCB DLBCLs,
40,47,57
targeted analyses of select alterations have
indicated that there is additional undefined genetic
complexity
27,49,58–60
and thus prompted further comprehensive
genetic studies.
5.1.3
|
Genetic heterogeneity of DLBCL
Initial genetic studies on DLBCL were focused on the discovery of
single genetic alterations, often in the context of COO‐defined
transcriptional subtypes.
1,27,61–65
Advances in genome‐wide tech-
nologies and integrative genomic analysis has allowed the charac-
terization of a more precise picture of the DLBCL genome, but
were either limited by focusing on single types of alterations,
sample size, clinical annotation, or the lack of data
integration.
29,30,40
To overcome these limitations, we integrated significant genetic
alterations composed of recurrent somatic mutations, SCNAs and
SVs, and discovered five genetically distinct DLBCL subsets
29
that
predicted outcome to state‐of‐the‐art frontline treatment, suggested
new insights into the lymphomagenesis of DLBCLs and suggested
rational combination treatment (Figure 2). These five subsets
included: (1) a high‐risk ABC DLBCLs with near‐uniform BCL2 copy
gain, frequent activating MYD88 and CD79B mutations and extra-
nodal tropism (C5 DLBCLs); (2) previously unappreciated favorable‐
risk ABC DLBCLs with genetic features of an extrafollicular, possibly
marginal zone origin (C1 DLBCLs); (3) poor‐risk GCB‐DLBCLs
with BCL2 SVs, inactivating mutations and/or copy loss of PTEN
and alterations of epigenetic enzymes (C3 DLBCLs); (4) a newly
defined group of good‐risk GCB DLBCLs with distinct alterations in
BCR/phosphoinositide 3‐kinase (PI3K), JAK/STAT and BRAF
pathway components and multiple histones (C4 DLBCLs); and (5) an
ABC/GCB‐independent group of tumors with biallelic inactivation
of TP53,9p21.3/CDKN2A and associated genomic instability
(C2 DLBCLs).
The biology of these five DLBCL subsets was largely confirmed
by an independent nonoverlapping large‐scale study that followed a
completely different analytical approach and discovered similar
groups with shared pathogenetic mechanisms.
30
In particular, C1
DLBCLs
29
were similar to BN2 (BCL6/NOTCH2),
30
C3 DLBCLs
29
were similar to EZB (EZH2/BCL2)
30
and C5 DLBCLs
29
were similar
to MCD (MYD88/CD79B) (Figure 2).
30
In subsequent work, the
biology of the remaining DLBCL subtypes (C2 and C4 DLBLCs) have
recently been also independently validated by two other groups
(C4 ∼ST2; C2 ∼A53 |C4 ∼SGK1; C2 ∼TP53) (Figure 2)
66,67
.
These studies underscore that DLBCL is a genetically heterogenous
disease with at least 5 different molecular subtypes. At the same
time, it also highlights, that despite having several hundreds of tu-
mors, we still do not capture the full spectrum of DLBCL subsets
and in particular for low‐frequency subtypes larger sample sizes are
needed.
Importantly, the genetic DLBCL subtypes has provided new
insights into the pathogenesis of these tumors with suggestions for
novel rational combination therapies and predict outcome.
29
In a
proof‐of‐concept study, it has been demonstrated that in cell line
models of C3 DLBCLs the combination of BCL‐2 and PI3Kα/δin-
hibitors cured 75% of the xenotransplanted mice, underscoring
that the new classification is a roadmap to genotype‐informed
targeted combination therapies.
29,68
More work is needed, to link
genetically defined subtypes to actionable vulnerabilities, and
eventually build molecular classifiers that link genetics to de-
pendencies with the hope of using them for precision medical
trials.
WIENAND AND CHAPUY
-
27
6
|
OUTLOOK/PERSPECTIVE
After several decades of empirical clinical trial design, we are reaching
a ceiling for clinical improvements in unselected patients.
69
For that
reason, it is important that technological advances lead to compre-
hensive genomic studies in informative and large LBCL cohorts, that
identify unique genetic signatures for discrete LBCL subtypes. The
derived genetic signatures, their temporal ordering and the associ-
ated mutational signatures and transcriptional profiles have aided in
better understanding of the associated biology and lymphomagenesis,
identified prognostic markers of response to standard induction
treatment and suggested rationally treatment combinations suited for
individual lymphoma subtypes. Importantly, new treatment modal-
ities are quickly moving into the clinics, including molecular subtype
agnostic therapies, such as CAR‐T cells, antibody–drug conjugates
and bi‐specific antibodies, but also other subtype‐specific (precision
medicine) approaches. Comprehensive genomic studies suggest that
within one lymphoma entity there are subtypes, which differ geneti-
cally as largely as two unrelated cancer types, while at the same time
there are shared genetic signatures across entities. This information
needs to be appreciated in next‐generation clinical trial designs (i.e.,
basket vs. umbrella trials). Many driver alterations of LBCL subtypes
encode for proteins that are readily druggable with small molecule
inhibitors or monoclonal antibodies and for LBCL subtypes that are
still poorly understood we need to create model systems, perform
functional screens (both genetic and pharmacological) and integrate
this information with other omics technologies, such as recently
suggested with microenvironmental immune signatures.
70
While the
last years were focused on bulk genomics, recent studies shed light on
the tremendous intratumoral heterogeneity within DLBCL
71
and pave
the way for the coming years. Eventually, molecular classifiers have
the potential to perform patient stratification in real‐time and in
clinical settings. We believe that the integration of bulk and single‐cell
omics technologies with large‐scale functional screens will help to
select more specific therapies for patients with high‐risk subtypes of
B‐cell lymphoma and thereby hopefully, bring precision medicine for
DLBCL to its full potential.
ACKNOWLEDGMENT
KW is supported by the BMBF SeneSys Consortium (031L0189B)
granted towards BC.
CONFLICT OF INTERESTS
The authors declare no potential conflict of interests.
PEER REVIEW
The peer review history for this article is available at https://publons.
com/publon/10.1002/HON.2847.
DATA AVAILABILITY STATEMENT
Not relevant.
REFERENCES
1. Swerdlow SH, Campo E, Pileri SA, et al. The 2016 revision of the
World Health Organization classification of lymphoid neoplasms.
Blood. 2016;127(20):2375‐2390.
2. Savage KJ, Monti S, Kutok JL, et al. The molecular signature of
mediastinal large B‐cell lymphoma differs from that of other diffuse
large B‐cell lymphomas and shares features with classical Hodgkin
lymphoma. Blood. 2003;102(12):3871‐3879.
3. Feuerhake F, Kutok JL, Monti S, et al. NFkappaB activity, function,
and target‐gene signatures in primary mediastinal large B‐cell lym-
phoma and diffuse large B‐cell lymphoma subtypes. Blood.
2005;106:1392‐1399.
4. Rosenwald A, Wright G, Leroy K, et al. Molecular diagnosis of pri-
mary mediastinal B cell lymphoma identifies a clinically favorable
FIGURE 2 Discovery of genetic DLBCL subtypes (A) with associated genetic, transcriptomic and prognostic features (B). DLBCL, diffuse
large B‐cell lymphoma
28
-
WIENAND AND CHAPUY
subgroup of diffuse large B cell lymphoma related to Hodgkin lym-
phoma. J Exp Med. 2003;198(6):851‐862.
5. Green MR, Monti S, Rodig SJ, et al. Integrative analysis reveals se-
lective 9p24.1 amplification, increased PD‐1 ligand expression, and
further induction via JAK2 in nodular sclerosing Hodgkin lymphoma
and primary mediastinal large B‐cell lymphoma. Blood. 2010;
116(17):3268‐3277.
6. Rui L, Emre NC, Kruhlak MJ, et al. Cooperative epigenetic modu-
lation by cancer amplicon genes. Cancer Cell. 2010;18(6):590‐605.
7. Y Hao, Chapuy B, Monti S, Sun HH, Rodig S, Shipp MA et al., Se-
lective JAK2 inhibition specifically decreases Hodgkin lymphoma
and mediastinal large B‐cell lymphoma growth in vitro and in vivo.
Clin Cancer Res. 2014;20(10):2674–83. https://doi.org/10.1158/
1078‐0432.CCR‐13‐3007
8. Chapuy B, Roemer MG, Stewart C, et al. Targetable genetic features
of primary testicular and primary central nervous system lym-
phomas. Blood. 2016;127(7):869‐881.
9. Green MR, Rodig S, Juszczynski J, et al. Constitutive AP‐1 activity
and EBV infection induce PD‐L1 in Hodgkin lymphomas and post-
transplant lymphoproliferative disorders: implications for targeted
therapy. Clin Cancer Res. 2012;18(6):1611‐1618.
10. Twa DD, Chan FC, Ben‐Neriah S, et al. Genomic rearrangements
involving programmed death ligands are recurrent in primary
mediastinal large B‐cell lymphoma. Blood. 2014;123(13):
2062‐2065.
11. Ansell SM, Lesokhin AM, Borrello I, et al. PD‐1 blockade with
nivolumab in relapsed or refractory Hodgkin's lymphoma. N Engl J
Med. 2014.372(4):311–319. https://doi.org/10.1056/NEJMoa141
1087
12. Younes A, Santoro A, Shipp M, et al. Nivolumab for classical Hodg-
kin's lymphoma after failure of both autologous stem‐cell trans-
plantation and brentuximab vedotin: a multicentre, multicohort,
single‐arm phase 2 trial. Lancet Oncol. 2016;17(9):1283‐1294.
13. Armand P, Shipp MA, Ribrag V, et al. Programmed death‐1 blockade
with pembrolizumab in patients with classical Hodgkin lymphoma
after brentuximab vedotin failure. J Clin Oncol. 2016;34(31):
3733‐3739.
14. Armand P, Chen YB, Redd RA, et al. PD‐1 blockade with pem-
brolizumab for classical Hodgkin lymphoma after autologous stem
cell transplantation. Blood. 2019;134(1):22‐29.
15. Zinzani PL, Ribrag CH, Moskowitz CH, et al. Safety and tolera-
bility of pembrolizumab in patients with relapsed/refractory pri-
mary mediastinal large B‐cell lymphoma. Blood. 2017;130(3):
267‐270.
16. Armand P, Rodig V, Melnichenko C, et al. Pembrolizumab in relapsed
or refractory primary mediastinal large B‐cell lymphoma. J Clin
Oncol. 2019;37(34):3291‐3299.
17. Chapuy B SC, Dunford AJ, Kim J, et al. Genomic analyses of PMBL
reveals new drivers and mechanisms of sensitivity to PD‐1 blockade.
Blood. 2019;134:2369‐2382.
18. Mottok A HSS, Chavez EA, Woolcock B, et al. Integrative genomic
analysis identifies key pathogenic mechanisms in primary medias-
tinal large B‐cell lymphoma. Blood. 2019;134:802‐813.
19. Wienand K, Chapuy B, Stewart C, et al. Genomic analyses of flow‐
sorted Hodgkin Reed‐Sternberg cells reveal complementary mech-
anisms of immune evasion. Blood Adv. 2019;3(23):4065‐4080.
20. Wang S, Jia M, He Z, Liu XS. APOBEC3B and APOBEC mutational
signature as potential predictive markers for immunotherapy
response in non‐small cell lung cancer. Oncogene. 2018;37(29):
3924‐3936.
21. Le DT, Uram JN, Wang H, et al. PD‐1 blockade in tumors with
mismatch‐repair deficiency. N Engl J Med. 2015;372(26):2509‐2520.
22. Rubenstein JL, Gupta NK, Mannis GN, Lamarre AK, Treseler P. How
I treat CNS lymphomas. Blood. 2013;122(14):2318‐2330.
23. Cheah CY, Wirth A, Seymour JF. Primary testicular lymphoma. Blood.
2013.123(4):486–493. https://doi.org/10.1182/blood‐2013‐10‐
530659
24. Deckert M, Montesinos‐Rongen M, Brunn A, Siebert R. Systems
biology of primary CNS lymphoma: from genetic aberrations to
modeling in mice. Acta Neuropathol. 2014;127(2):175‐188.
25. Fukumura K, Kawazu M, Kojima T, et al. Genomic characterization of
primary central nervous system lymphoma. Acta Neuropathol
2016;131:865‐875.
26. Nayak L, Iwamoto FM, LaCasce A, et al. PD‐1 blockade with nivo-
lumab in relapsed/refractory primary central nervous system and
testicular lymphoma. Blood. 2017;129(23):3071‐3073.
27. Monti S, Chapuy B, Takeyama K, et al. Integrative analysis reveals an
outcome‐associated and targetable pattern of p53 and cell cycle
deregulation in diffuse large B cell lymphoma. Cancer Cell.
2012;22(3):359‐372.
28. Davis RE, Ngo VN, Lenz G, et al. Chronic active B‐cell‐receptor
signalling in diffuse large B‐cell lymphoma. Nature. 2010;
463(7277):88‐92.
29. Chapuy B, Stewart C, Dunford AJ, et al. Molecular subtypes of
diffuse large B cell lymphoma are associated with distinct patho-
genic mechanisms and outcomes. Nat Med. 2018;24(5):679‐690.
30. Schmitz R, Wright GW, Huang DW, et al. Genetics and pathogenesis
of diffuse large B‐cell lymphoma. N Engl J Med. 2018;378(15):1396‐
1407.
31. Phelan JD, Young RM, Webster DE, et al. A multiprotein super-
complex controlling oncogenic signalling in lymphoma. Nature.
2018;560:387‐391.
32. Thurner L, Preuss KD, Bewarder M, et al. Hyper‐N‐glycosylated
SAMD14 and neurabin‐I as driver autoantigens of primary central
nervous system lymphoma. Blood. 2018;132(26):2744‐2753.
33. Chapuy B. Tropism of PCNSL: is it all about autoantigens?. Blood.
2018;132(26):2704‐2706.
34. Lionakis MS, Dunleavy K, Roschewski M, et al. Inhibition of B cell
receptor signaling by ibrutinib in primary CNS lymphoma. Cancer
Cell. 2017;31(6):833‐843.e835.
35. Grommes C, Pastore A, Palaskas N, et al. Ibrutinib unmasks critical
role of bruton tyrosine kinase in primary CNS lymphoma. Cancer
Discov. 2017;7(9):1018‐1029.
36. Sesques P, Johnson NA. Approach to the diagnosis and treatment of
high‐grade B‐cell lymphomas with MYC and BCL2 and/or BCL6
rearrangements. Blood. 2017;129(3):280‐288.
37. Horn H, Ziepert M, Becher C, et al. MYC status in concert with BCL2
and BCL6 expression predicts outcome in diffuse large B‐cell lym-
phoma. Blood. 2013;121(12):2253‐2263.
38. Johnson NA, Slack GW, Savage KJ, et al. Concurrent expression of
MYC and BCL2 in diffuse large B‐cell lymphoma treated with rit-
uximab plus cyclophosphamide, doxorubicin, vincristine, and pred-
nisone. J Clin Oncol. 2012;30:3452‐3459.
39. Green TM, Young KH, Visco C, et al. Immunohistochemical double‐
hit score is a strong predictor of outcome in patients with diffuse
large B‐cell lymphoma treated with rituximab plus cyclophospha-
mide, doxorubicin, vincristine, and prednisone. J Clin Oncol.
2012;30(28):3460‐3467.
40. Reddy A, Zhang J, Davis NS, et al. Genetic and functional drivers of
diffuse large B cell lymphoma. Cell. 2017;171(2):481‐494.e15.
41. Rosenwald A, Sehn LH, Maucort‐Boulch D. Prognostic significance of
<em>MYC</em>single, double, triple hit and <em>MYC</em>‐
Translocation partner status in diffuse large B‐cell lymphoma—a
study by the Lunenburg lymphoma biomarker consortium (LLBC).
Blood. 2018;132(Supp 1):344–344.
42. Shipp MA, Harrington DP, Anderson JR, et al. A predictive model for
aggressive non‐Hodgkin's lymphoma. N Engl J Med. 1993;329(14):
987‐994.
WIENAND AND CHAPUY
-
29
43. Sehn LH, Berry B, Chhanabhai M, et al. The Revised International
Prognostic Index (R‐IPI) is a better predictor of outcome than the
standard IPI for patients with diffuse large B‐cell lymphoma treated
with R‐CHOP. Blood. 2007;109(5):1857‐1861.
44. Hartmann S, Doring C, Vucic E, et al. Array comparative genomic
hybridization reveals similarities between nodular lymphocyte pre-
dominant Hodgkin lymphoma and T cell/histiocyte rich large B cell
lymphoma. Br J Haematol. 2015;169(3):415‐422.
45. Chen BJ, Chapuy B, Ouyang J, et al. PD‐L1 expression is charac-
teristic of a subset of aggressive B‐cell lymphomas and virus‐asso-
ciated malignancies. Clin Cancer Res. 2013;19(13):3462‐3473.
46. Griffin GK, Roemer MGM, Lipschitz M, et al. Integrated genetic and
topological analysis reveals a Hodgkin‐like mechanism of immune
escape in T‐cell/histiocyte‐rich large B‐cell lymphoma. Blood.
2018;132(S1):1579–1579.
47. Rosenwald A, Wright G, Chan WC, et al. The use of molecular
profiling to predict survival after chemotherapy for diffuse large‐B‐
cell lymphoma. N Engl J Med. 2002;346(25):1937‐1947.
48. Monti S, Savage KJ, Kutok JL, et al. Molecular profiling of diffuse
large B‐cell lymphoma identifies robust subtypes including one
characterized by host inflammatory response. Blood. 2005;105(5):
1851‐1861.
49. Ngo VN, Young RM, Schmitz R, et al. Oncogenically active MYD88
mutations in human lymphoma. Nature. 2011;470(7332):115‐119.
50. Caro P, Kishan U, Norberg IA, et al. Metabolic signatures uncover
distinct targets in molecular subsets of diffuse large B cell lym-
phoma. Cancer Cell. 2012;22(4):547‐560.
51. Chen L, Monti S, Juszczynski J, et al. SYK inhibition modulates
distinct PI3K/AKT‐dependent survival pathways and cholesterol
biosynthesis in diffuse large B cell lymphomas. Cancer Cell.
2013;23(6):826‐838.
52. Basso K, Dalla‐Favera R. Germinal centres and B cell lymphoma-
genesis. Nat Rev Immunol. 2015;15:172‐184.
53. Alizadeh AA, Eisen MB, Davis C, et al. Distinct types of diffuse large
B‐cell lymphoma identified by gene expression profiling. Nature.
2000;403(6769):503‐511.
54. Norberg E, Lako A, Chen PH, et al. Differential contribution of the
mitochondrial translation pathway to the survival of diffuse large B‐
cell lymphoma subsets. Cell Death Differ. 2017;24(2):251‐262.
55. Hans CP, Weisenburger DD, Greiner TC, et al. Confirmation of
the molecular classification of diffuse large B‐cell lymphoma by
immunohistochemistry using a tissue microarray. Blood. 2004;
103(1):275‐282.
56. Scott DW, Wright GW, Williams PM, et al. Determining cell‐of‐origin
subtypes of diffuse large B‐cell lymphoma using gene expression in
formalin‐fixed paraffin‐embedded tissue. Blood. 2014;123(8):
1214‐1217.
57. Lenz G, Wright G, Dave S, et al. Stromal gene signatures in large‐B‐
cell lymphomas. N Engl J Med. 2008;359(22):2313‐2323.
58. Pfeifer M, Grau M, Lenze D, et al. PTEN loss defines a PI3K/AKT
pathway‐dependent germinal center subtype of diffuse large B‐cell
lymphoma. Proc Natl Acad Sci U. S. A. 2013;110(30):12420‐12425.
59. Dubois S, Viailly PJ, Bohers E, et al. Biological and clinical relevance
of associated genomic alterations in MYD88 L265P and non‐L265P‐
mutated diffuse large B‐cell lymphoma: analysis of 361 cases. Clin
Cancer Res. 2017;23(9):2232‐2244.
60. Ennishi D, Mottok A, Ben‐Neriah S, et al. Genetic profiling of MYC
and BCL2 in diffuse large B‐cell lymphoma determines cell‐of‐origin‐
specific clinical impact. Blood. 2017;129(20):2760‐2770.
61. Lenz G, Staudt LM. Aggressive lymphomas. N Engl J Med.
2010;362:1417‐1429.
62. Lenz G, Wright GW, Emre NC, et al. Molecular subtypes of diffuse
large B‐cell lymphoma arise by distinct genetic pathways. Proc Natl
Acad Sci U. S. A. 2008;105(36):13520‐13525.
63. Pasqualucci L, Trifonov V, Fabbri G, et al. Analysis of the coding
genome of diffuse large B‐cell lymphoma. Nat Genet.
2011;43(9):830‐837.
64. Morin RD, Mendez‐Lago M, Mungall AJ, et al. Frequent mutation of
histone‐modifying genes in non‐Hodgkin lymphoma. Nature. 2011;
476(7360):298‐303.
65. Lohr JG, Stojanov P, Lawrence MS, et al. Discovery and prioritization
of somatic mutations in diffuse large B‐cell lymphoma (DLBCL) by
whole‐exome sequencing. Proc Natl Acad Sci U. S. A.
2012;109(10):3879‐3884.
66. Wright G HDW, Phelan JD, Coulibaly ZA, et al. A probabilistic
classification tool for genetic subtypes of diffuse large B cell lym-
phoma with therapeutic implications. Cancer Cell. 2020;37:551‐568.
67. Lacy S SE, Beer BSL, Painter D, et al. Targeted sequencing in DLBCL,
molecular subtypes, and outcomes: a Haematological Malignancy
Research Network Report. Blood. 2020;135(20):1759‐1771.
68. Bojarczuk K, Wienand K, Ryan JA, et al. Targeted inhibition of
PI3Kalpha/delta is synergistic with BCL‐2 blockade in genetically
defined subtypes of DLBCL. Blood. 2018;133(1):70‐80.
69. Goy A. Succeeding in breaking the R‐CHOP ceiling in DLBCL:
Learning from negative trials. J Clin Oncol. 2017;35(31):3519‐3522.
70. Dufva O, Polonen P, Bruck O, et al. Immunogenomic landscape of
hematological malignancies. Cancer Cell. 2020;38(3):380‐399.e13.
71. Roider T, Seufert J, Uvarovskii A, et al. Dissecting intratumour
heterogeneity of nodal B‐cell lymphomas at the transcriptional, ge-
netic and drug‐response levels. Nat Cell Biol. 2020;22(7):896‐906.
How to cite this article: Wienand K, Chapuy B. Molecular
classification of aggressive lymphomas—past, present, future.
Hematological Oncology. 2021;39(S1):24–30. https://doi.org/
10.1002/hon.2847
30
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WIENAND AND CHAPUY
Received: 3 March 2021
DOI: 10.1002/hon.2860
SUPPLEMENT ARTICLE
Mantle cell lymphoma—Advances in molecular biology,
prognostication and treatment approaches
Elisabeth Silkenstedt |Martin Dreyling
Department of Medicine III, LMU Hospital,
Munich, Germany
Correspondence
Martin Dreyling, Oberarzt der Klinik,
Medizinische Klinik III, LMU Klinikum,
Marchioninistrasse 15, 81377 München,
Germany.
Email: Martin.Dreyling@med.uni-muenchen.de
Funding information
Open Access funding enabled and organized
by Projekt DEAL.
Abstract
Mantle cell lymphoma (MCL) is clinically characterized by its heterogenous behavior
with courses ranging from indolent cases that do not require therapy for years to
highly aggressive MCL with very limited prognosis. A better understanding of the
complex biology of MCL has already led to the approval of several innovative
agents, expanding the landscape of MCL therapies and improving therapeutic op-
tions especially for refractory or relapsed disease. Nevertheless, to further optimize
MCL treatment, early identification of individual risk profile and risk‐adapted,
patient‐tailored choice of therapeutic strategy needs to be prospectively incorpo-
rated in clinical patient management. This review highlights recent advances in
deciphering the molecular background of MCL, the definition of prognostically
relevant factors and the identification of potential druggable targets and summa-
rizes current treatment recommendations for primary and relapsed/refractory MCL
including novel targeted therapies.
KEYWORDS
genetics, mantle cell lymphoma, pathogenesis, prognostication, therapy
1
|
INTRODUCTION
Mantle cell lymphoma (MCL) is clinically characterized by its heter-
ogenous behavior with courses ranging from indolent cases that do
not require therapy for years to highly aggressive MCL with very
limited prognosis.
1
Patients typically present with lymphadenopathy
of several sites, most of the patients are diagnosed with advanced
stage disease (Ann Arbor stage III, IV). Extranodal manifestations
occur in 90% of patients, including infiltration of bone marrow (53%–
82%), blood (50%), liver (25%), and the gastrointestinal tract (20%–
60%).
1,2
The spleen is enlarged in 40% of patients.
1
In some cases,
leukemic manifestation in combination with massive splenomegaly is
clinically prominent. These nonnodal, leukemic cases are often
characterized by a more indolent clinical course. Accordingly, in the
WHO 2016 update of lymphoid malignancies, MCL now consists
of two distinct categories.
3
Nodal MCL (80%–90% of cases) is
characterized by unmutated immunoglobulin heavy chain variable
region genes (IGHV), sex‐determining region Y‐box 11 (SOX11)
overexpression and a generally more aggressive clinical behavior.
Nonnodal leukemic MCL (10%–20% of cases) typically displays
mutated IGHV, SOX11 negativity and presents with indolent bio-
logical behavior. Histologically, besides “classical” MCL, pleomorphic
and blastoid variants can be distinguished.
3
MCL with blastoid
morphology often features high proliferation rates, displaying a more
aggressive clinical course.
3,4
Traditionally, MCL was associated with a poor prognosis with a
median overall survival (OS) of 3–5 years. However, major advances
in the treatment of MCL patients have been achieved over the last
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Hematological Oncology. 2021;39(S1):31–38. wileyonlinelibrary.com/journal/hon
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31
years, especially by the development of an induction immunoche-
motherapy including cytarabine and anti‐CD20 antibodies and by
introducing a consolidation high‐dose therapy with autologous stem
cell transplantation (ASCT).
5
Moreover, introduction of rituximab as
maintenance therapy, especially for those patients not eligible for
high‐dose therapy, significantly improved survival rates in this group
of patients.
6
Yet, long‐term prognosis is still limited and patients with
relapsed/refractory disease usually have a dismal outcome. There-
fore, improved understanding of cellular and molecular biology of
MCL and identification of relevant factors determining prognosis to
optimally use risk‐adapted treatment approaches will be critical to
further improve outcomes in this disease.
2
|
PATHOGENESIS AND MOLECULAR BIOLOGY
The development of MCL is the result of a complex pathogenetic
interplay between cellular and microenvironmental processes.
Genetic hallmark of MCL and considered the primary oncogenic
event in the pathogenesis is the chromosomal t(11;14)(q13;q32)
translocation, leading to overexpression of cyclin D1 and dysregula-
tion of cell cycle at the G1–S phase transition.
7
Cyclin D1 negative
MCLs usually carry CCND2/CCND3 rearrangements with immuno-
globulin genes instead. A subset of cyclin D1
−
/D2
−
/D3
−
MCL with
aggressive features has cyclin E dysregulation. In these rare cyclin
D1‐negative cases, immunohistochemistry for SOX‐11 is especially
helpful to confirm the diagnosis.
The transcription factor SOX‐11 is overexpressed in more than
90% of MCL cases, whereas a leukemic nonnodal variant, resembling
chronic lymphocytic leukemia (CLL), lacks SOX‐11 expression and is
associated with a more indolent course.
8
In this subset of patients
with leukemic, nonnodal presentation, SOX‐11 expression proved to
be prognostically relevant, identifying a favorable outcome in pa-
tients with negative SOX‐11 with mutated IGHV.
The constitutive activation of the B‐cell receptor and its multiple
downstream signaling pathways also plays an important role in the
development of the disease.
7
Furthermore, genomic profiling revealed a high number of sec-
ondary genetic alterations and recurrent mutations affecting for
example regulation of cell cycle, DNA damage response and apoptosis
pathways that contribute to the pathogenesis and aggressiveness of
MCL.
7
In recent years, next generation sequencing approaches to
unravel the genetic background of MCL led to the identification
of numerous recurrent somatic mutations including genes involved
in genotoxic stress pathways (ATM,TP53,CDKN2A), epigenetic
regulators (WHSC1,KMT2D,MEF2B,KMT2C,SMARCA4,SMARCB1)
and genes regulating DNA replication (SAMHD1), RNA processing
(HNRNPH1) as well as cell homeostasis, cell growth and cell
death (CCND1,TP53,CDKN2A,CDKN1B,BIRC3,CARD11,TRAF2,
RB1,POT1,NOTCH1/2).
9
Yet, functional relevance remains un-
clear for most of the mutations and is currently under further
investigation.
3
|
PROGNOSTIC FACTORS
Important clinical and serological factors, associated with a worse
clinical outcome include age, poor general condition, advanced stage
of disease (Ann Arbor stage III or IV), splenomegaly and anemia, the
serum level of β2‐microglobulin and lactate dehydrogenase (LDH),
blastoid cytology, extranodal presentation, and constitutional
symptoms.
A prognostic score that has been confirmed in numerous series,
the MCL International Prognostic Index (MIPI), was established
implementing four independent prognostic factors: age, performance
status, LDH, and leukocyte count.
10
Yet, the most important prognostic markers independent of
clinical features are the proliferation rate as measured by Ki‐67
expression and the expression of p53. These two (p53 high and
Ki67 >30%), together with blastoid morphology, were recently
reported to define a high‐risk biology with significantly shorter
failure‐free and OS. Immunohistochemical determination of Ki‐67
expression has been prospectively confirmed as a reliable prog-
nostic marker and is, in combination with the MIPI (MIPI‐c), a
highly recommended tool to estimate individual risk profile and to
identify high‐risk patients (Ki‐67 >30%) who may qualify for more
aggressive therapeutic approaches.
11
Furthermore, a cell prolifer-
ation gene signature (MCL35) that distinguishes patient subsets
that differ by more than 5 years in median survival has been
identified.
Deletions of 17p13 or mutations of TP53 as well as deletions of
CDKN2A were reported to be associated with worse clinical
outcome in the majority of the studies published. Despite treated
with high‐dose cytarabine and ASCT, younger MCL patients
with deletions of CDKN2A (p16) and TP53 show an unfavorable
prognosis. Furthermore, TP53 mutations were significantly associ-
ated with high Ki67 (>30%), blastoid morphology, MIPI high‐
risk, and inferior responses to both induction‐and high‐dose
chemotherapy.
12
Other genetic lesions with inferior outcomes include mutations
in the NOTCH genes and in KMT2D as well as MYC alterations and
mutations in WHSC1 and CCND1.
Prognostic markers ‐current and future ‐are summarized in
Table 1.
Concerning the prognostic impact of minimal residual disease
(MRD) status, several studies have been published, providing evi-
dence of the strong prognostic potential of MRD status predicting
improved subsequent progression‐free survival (PFS) for MRD‐
negative patients at the end of induction and before high‐dose
consolidation.
5
In addition, lack of molecular remission after end of
currently recommended standard treatment was shown to be
strongly predictive for early clinical relapse within 1–2 years.
5,13
However, so far use of MRD analysis is restricted to clinical trials.
Furthermore, the impact of MRD monitoring in the context of the
new‐targeted treatments, such as the Bruton's tyrosine kinase (BTK)
inhibitor ibrutinib, remains unclear.
32
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SILKENSTEDT AND DREYLING
3.1
|
Therapy in patients ≤65 years
3.1.1
|
Induction: Dose‐intensified, cytarabine‐
containing regimen
The administration of the R‐CHOP/DHAP regimen compared to
administration of R‐CHOP alone prior to myelo‐ablative consolida-
tion with ASCT more than doubled time to treatment failure (TTF)
(109 vs. 47 months).
5
We do not recommend an additional routine
central nervous system prophylaxis.
Another commonly used treatment approach, predominantly
applied in the USA, is the intensive chemo‐immunotherapy regimen
rituximab in combination with hyper‐CVAD. This regimen achieved
high complete response (CR) rates and long‐term remissions and does
not require consolidation with ASCT. However, this regimen is
hampered by significant therapy‐associated toxicity, including sec-
ondary malignancies, and should only be considered in young, fit
patients.
3.1.2
|
Consolidation: ASCT
In several studies, the addition of high‐dose consolidation followed
by ASCT resulted in impressive survival rates.
5,14
A large randomized
trial proved that consolidation by myeloablative radiochemotherapy
followed by ASCT in first remission significantly prolonged PFS (3.3
vs. 1.5 years) and OS
15
independently of the addition of rituximab.
Unfortunately, even after such intensive consolidation regimen, a
majority of patient's relapse.
3.1.3
|
Maintenance
Rituximab maintenance after ASCT is currently considered standard
of care for younger patients with MCL based on the results of a large
phase III trial showing a significant optimization of PFS (83% vs. 64%
after 4 years) and OS (89% vs. 80% after 4 years) after 3 years of
rituximab maintenance compared to observation only.
14
Recently, another phase III trial revealed a benefit from a
lenalidomide maintenance after autologous transplantation with
improved PFS (80% vs. 64% after 3 years) compared to observa-
tion.
16
However, due to the elevated toxicity profile (especially
hematotoxicity), lenalidomide maintenance should be only applied to
patients not suitable to receive rituximab.
Figure 1suggests a risk‐adapted treatment strategy for patients
≤65 years.
3.2
|
Therapy in patients more than 65 years
3.2.1
|
Induction
The group of the over 65 year olds ineligible for transplantation
presents very heterogenous regarding physical and cognitive per-
formance. A suggested therapeutic algorithm is depicted in Figure 2.
Fit patients greater than 65 years should receive conventional
immunochemotherapy followed by rituximab maintenance.
6
The VR‐
CAP regimen recently proved to be superior over R‐CHOP in a large
International phase III trial with a doubled OS after 82 months (90.7
vs. 45.7 months). However, hematologic toxicity (especially >Grade 3
thrombopenia) was significantly increased in the experimental arm
(57% vs. 6%).
17
The R‐BAC scheme offers another useful option. Yet,
this regimen was accompanied by severe hepatotoxicities and should
therefore only be administered to very fit older patients with high‐
risk features (e.g., blastoid variant, high LDH count).
18
Alterna-
tively, for patients not qualifying for such intensive therapy regi-
mens, R‐Bendamustine offers an appropriate alternative. This
combination resulted in similar response rates (93% vs. 91%)
compared to R‐CHOP and was even superior in PFS (35 vs. 21
months) with a more favorable toxicity profile observed.
19
Taken
TABLE 1Prognostic markers—
current and future In clinical routine Potential for future use
Age “MCL35” RNA expression analysis
Performance status SOX11 expression
Central nervous system involvement at diagnosis TP53 mutations/deletions by sequencing
analysis
Stage of disease (I and II vs. III and IV) MRD testing
Serum level of β2‐microglobulin and LDH
Morphology (classic vs. blastoid)
MIPI
Ki67 (<30% vs. >30%)
TP53 expression by immunohistochemistry
Abbreviations: LDH, lactate dehydrogenase; MIPI, MCL International Prognostic Index; MRD,
minimal residual disease.
SILKENSTEDT AND DREYLING
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33
FIGURE 1 Suggested therapeutic algorithm
34
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SILKENSTEDT AND DREYLING
together, VR‐CAP and bendamustine–rituximab (BR) represent the
current standard approaches in older patients not eligible for high‐
dose therapy, who represent the majority of MCL patients. VR‐
CAP should be preferably considered for patients with a higher
risk‐profile such as high Ki‐67 expression or blastoid morphology. BR
may be preferable especially in patients with a more indolent CLL‐
like presentation.
3.2.2
|
Maintenance
A large, randomized, European phase III trial compared rituximab
maintenance to interferon (IFN) maintenance, confirming superiority
of rituximab as maintenance therapy. In this study, after four years,
58% of the patients receiving rituximab after induction therapy with
R‐CHOP were in remission, compared to 29% in the IFN arm
(p=0.01). PFS and OS were also significantly improved in the Rit-
uximab arm (5‐years PFS R vs. IFN 51% vs. 22%, 5 years OS R vs. IFN
79% vs. 59%).
20
Based on these results, rituximab maintenance after
R‐CHOP is now generally recommended. Although investigation of
the additional benefits of rituximab maintenance therapy after BR
chemotherapy is pending, we recommend a similar approach.
4
|
RECURRENT AND REFRACTORY DISEASE
4.1
|
Molecular‐targeted therapies
Several targeted therapy approaches have been investigated in
different studies as single agents or in combination with immu-
nochemotherapies or other targeted therapies (Table 2).
Targeting the B‐cell receptor pathway with the BTK inhibitor
ibrutinib resulted in the highest response rates of all targeted ap-
proaches so far leading to its approval in relapsed MCL. In a large
International phase II study, response rates of 68% were achieved
with ibrutinib in patients with relapsed disease.
21
The combination
FIGURE 2 Suggested therapeutic algorithm for patients greater than 65 years
SILKENSTEDT AND DREYLING
-
35
with rituximab was effective in all cases with low Ki‐67, whereas in
highly proliferating disease, only half of the patients responded to
this approach.
22
A pooled analysis of the results of three different
trials testing ibrutinib as monotherapy revealed overall response
rates of 66% with median PFS and OS of 12.8, respectively 25
months.
23
Ibrutinib given in combination with bendamustine and
rituximab in patients 65 years of age or older with newly diagnosed
MCL is currently being evaluated in the phase 3 SHINE trial
(NCT01776840). However, interindividual responsiveness is heter-
ogenous and primary and secondary resistance has been reported
with poor clinical outcome.
24
In patients with mutations in the P53
gene, median PFS was shown to be significantly worse. Patients
suffering early relapses after ibrutinib therapy demonstrated very
aggressive clinical courses.
24
Second generation BTK inhibitor acalabrutinib was approved in
October 2017 by the Food and Drug Administration (FDA) for pa-
tients with relapsed/refractory MCL who had received at least one
prior therapy as promising results, especially regarding tolerability,
were observed in an open‐label phase 2 study.
25
Acalabrutinib in
combination with BR compared to BR alone in previously untreated
MCL patients more than 65 years of age is currently evaluated in an
ongoing phase‐3 study (NCT02972840).
Next‐generation BTK‐inhibitor zanubrutinib is a highly potent, se-
lective, bioavailable, and irreversible BTK inhibitor with maximized
BTK occupancy. It was approved in 2019 in the United States and
China for the treatment of patients with R/R MCL based on results
from a phase II study in Chinese patients with R/R MCL reporting
high overall response rates with durable CRs and improved safety
and tolerability over existing treatments. The potential for use of
zanubrutinib in the first‐line setting is currently under evaluation in
the randomized phase III MANGROVE study (NCT04002297) in
which patients with treatment‐naive MCL will receive zanu-
brutinib +rituximab or bendamustine +rituximab.
For patients suffering early relapses after ibrutinib therapy, a
monotherapy with the B‐cell‐lymphoma 2‐inhibitor Abt‐199 (ven-
etoclax) might be a promising alternative, as a phase I trial showed
response rates of 75% in patients with relapsed MCL and 60% in
patients having received prior ibrutinib therapy. Recently, the com-
bination of ibrutinib and venetoclax proved to be highly effective in a
small study cohort.
26
The potential advantage of ibrutinib combined
with venetoclax over ibrutinib alone is currently being examined in
an ongoing phase‐3 study (SYMPATICO) (NCT03112174).
Various studies confirmed a benefit of the orally available
immunomodulatory drug lenalidomide in relapsed MCL, with response
rates of 35%–50%. In a randomized phase II trial, this approach was
superior to monochemotherapy (response rate 46% vs. 23%). Based
on an in vitro synergism, lenalidomide in combination with rituximab
resulted in long lasting remissions in first‐line therapy of a rather low
risk patient cohort.
27
This approach may be applied especially in
patients with contraindications against BTK inhibitors.
4.2
|
Allogeneic transplantation versus CAR T‐cells
For younger high‐risk patients with TP53—mutated and relapsed MCL,
who are transplant—eligible, the option of allogeneic transplantation
TABLE 2Molecular targeted therapies in MCL
Regimen Phase Number of patients ORR (CR) % Median PFS (months)
Lenalidomide Phase II 134 28 (7.5 ) 4
Lenalidomide Phase II 57 35
12
8.8
Lenalidomide versus. Phase II 170 46
11
8.7
Monochemotherapy 84 23
8
5.2
Lenalidomid +rituximab Phase II 44 57 (36) 11.1
Lenalidomid +rituximab Phase II 38 64% (After 5 years)
Ibrutinib Phase II 111 68
21
13.9
Ibrutinib vs. temsirolimus Phase III 280 72
19
14.6
40
1
6.2
Ibrutinib +rituximab Phase II 50 88 (44)
Ibrutinib +lenalidomid +rituximab Phase II 50 76 (56)
Idelalisib Phase I 40 40
5
3.7
Abt‐199 (venetoclax) Phase I 28 75
21
14
Abt‐199 (venetoclax) +ibrutinib Phase II 24 71
Acalabrutinib Phase II 124 81 (40)
Zanubrutinib Phase II 86 84 (68.6) 22.1
Abbreviations: CR, complete response; MCL, mantle cell lymphoma; ORR, overall response rate; OS, overall survival; PFS, progression‐free survival.
36
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SILKENSTEDT AND DREYLING
could be considered. Reduced‐intensity allogeneic stem cell trans-
plantation resulted in long‐term disease‐free survival in about 30% of
the patients and may be applicable also in patients older than age 60
years. Yet, transplantation‐associated severe acute and delayed tox-
icities, including chronic graft versus host disease and 20%–25%
treatment‐related mortality are frequent. Therefore, allogeneic
transplantation is not recommended in the first‐line setting and should
only be discussed in relapsed disease.
1
Recently, the FDA has approved the autologous CD19 CAR T‐cell
construct brexucabtagene autoleucel (formerly KTE‐X19; Tecartus),
based on results of the ZUMA‐2 trial, evaluating safety and efficacy of
this CD19 CAR T‐cell construct in patients with R/R MCL. Treatment
with brexucabtagene autoleucel resulted in the induction of durable
remissions, although serious and life‐threatening toxic events were
reported.
28
Another CD19‐directed CAR T‐cell product (Lisocabta-
gene Maraleucel) for relapsed/refractory MCL is currently being
evaluated in the ongoing Phase 1 study TRANSCEND NHL 001
(NCT02631044). Overall, results are promising and CAR T‐cell con-
structs may have also the potential to cure MCL patients. Yet, much
longer follow‐up is needed.
ACKNOWLEDGMENTS
Open Access funding enabled and organized by Projekt DEAL.
CONFLICT OF INTEREST
MD received (institutional) research support from Abbvie, Bayer,
Celgene, Janssen, Roche and honoraria for scientific advisory
boards and speaker's honoraria from Amgen, Astra Zeneca,
Bayer, Beigene, Celgene, Genmab, Gilead, Incyte, Janssen, Novartis,
Roche.
REFERENCES
1. Dreyling M, Campo E, Hermine O, et al. Newly diagnosed and
relapsed mantle cell lymphoma: ESMO clinical practice guidelines for
diagnosis, treatment and follow‐up. Ann Oncol. 2017;28(suppl_4):
iv62‐iv71.
2. Romaguera JE, Medeiros LJ, Hagemeister FB, et al. Frequency of
gastrointestinal involvement and its clinical significance in mantle
cell lymphoma. Cancer. 2003;97(3):586‐591.
3. Swerdlow SH, Campo E, Harris NL, et al. WHO Classification of
Tumours of Haematopoietic and Lymphoid Tissues. Vol. 2, 4th ed. Lyon,
France: IARC Publications; 2017.
4. Hoster E, Rosenwald A, Berger F, et al. Prognostic value of Ki‐67 index,
cytology, and growth pattern in mantle‐cell lymphoma: results from
randomized trials of the European Mantle Cell Lymphoma Network. J
Clin Oncol. 2016;34(12):1386‐1394.
5. Hermine O, Hoster E, Walewski J, et al. Addition of high‐dose
cytarabine to immunochemotherapy before autologous stem‐cell
transplantation in patients aged 65 years or younger with mantle
cell lymphoma (MCL Younger): a randomised, open‐label, phase 3
trial of the European Mantle Cell Lymphoma Network. Lancet.
2016;388(10044):565‐575.
6. Kluin‐Nelemans HC, Hoster E, Hermine O, et al. Treatment of older
patients with mantle‐cell lymphoma. N Engl J Med. 2012;367(6):
520‐531.
7. Jares P, Colomer D, Campo E. Molecular pathogenesis of mantle cell
lymphoma. J Clin Invest. 2012;122(10):3416‐3423.
8. Fernandez V, Salamero O, Espinet B, et al. Genomic and gene
expression profiling defines indolent forms of mantle cell lymphoma.
Cancer Res. 2010;70(4):1408‐1418.
9. Hill HA, Qi X, Jain P, et al. Genetic mutations and features of mantle
cell lymphoma: a systematic review and meta‐analysis. Blood Adv.
2020;4(13):2927‐2938.
10. Hoster E, Dreyling M, Klapper W, et al. A new prognostic index
(MIPI) for patients with advanced‐stage mantle cell lymphoma.
Blood. 2008;111(2):558‐565.
11. Aukema SM, Hoster E, Rosenwald A, et al. Expression of TP53 is
associated with the outcome of MCL independent of MIPI and Ki‐67
in trials of the European MCL Network. Blood. 2018;131(4):
417‐420.
12. Eskelund CW, Dahl C, Hansen JW, et al. TP53 mutations identify
younger mantle cell lymphoma patients who do not benefit
from intensive chemoimmunotherapy. Blood. 2017;130(17):1903‐
1910.
13. Pott C, Hoster E, Delfau‐Larue M‐H, et al. Molecular remission is an
independent predictor of clinical outcome in patients with mantle
cell lymphoma after combined immunochemotherapy: a European
MCL intergroup study. Blood. 2010;115(16):3215‐3223.
14. Le Gouill S, Thieblemont C, Oberic L, et al. Rituximab after autolo-
gous stem‐cell transplantation in mantle‐cell lymphoma. N Engl J
Med. 2017;377(13):1250‐1260.
15. Zoellner A, Unterhalt M, Stilgenbauer S, et al. Autologous stem cell
transplantation in first remission significantly prolongs progres
sion‐free and overall survival in mantle cell lymphoma. Interna-
tional Conference on Malignant Lymphoma; 2019; Lugano,
Switzerland.
16. Ladetto M, Ferrero S, Evangelista A, et al. Lenalidomide main-
tenance after autologous transplantation prolongs PFS in young
MCL patients: results of the randomized phase III MCL 0208
trial from Fondazione Italiana Linfomi (FIL). Blood.
2018;132:401.
17. Robak T, Jin J, Pylypenko H, et al. Frontline bortezomib, rituximab,
cyclophosphamide, doxorubicin, and prednisone (VR‐CAP) versus
rituximab, cyclophosphamide, doxorubicin, vincristine, and predni-
sone (R‐CHOP) in transplantation‐ineligible patients with newly
diagnosed mantle cell lymphoma: final overall survival results of a
randomised, open‐label, phase 3 study. Lancet Oncol. 2018;19(11):
1449‐1458.
18. Visco C, Chiappella A, Nassi L, et al. Rituximab, bendamustine, and
low‐dose cytarabine as induction therapy in elderly patients with
mantle cell lymphoma: a multicentre, phase 2 trial from Fondazione
Italiana Linfomi. Lancet Haematol. 2017;4(1):e15‐e23.
19. Rummel MJ, Niederle N, Maschmeyer G, et al. Bendamustine plus
rituximab versus CHOP plus rituximab as first‐line treatment for
patients with indolent and mantle‐cell lymphomas: an open‐label,
multicentre, randomised, phase 3 non‐inferiority trial. Lancet.
2013;381(9873):1203‐1210.
20. Kluin‐Nelemans HC, Hoster E, Hermine O, et al. Treatment of older
patients with mantle cell lymphoma: long‐term follow‐up of the
randomized European MCL Elderly trial. J Clin Oncol. 2020;38(3):
248–256.
21. Wang ML, Rule S, Martin P, et al. Targeting BTK with ibrutinib in
relapsed or refractory mantle‐cell lymphoma. N Engl J Med. 2013;
369(6):507‐516.
22. Wang ML, Lee H, Chuang H, et al. Ibrutinib in combination with
rituximab in relapsed or refractory mantle cell lymphoma: a
single‐centre, open‐label, phase 2 trial. Lancet Oncol. 2016;17(1):
48‐56.
23. Rule S, Dreyling M, Goy A, et al. Ibrutinib for the treatment of
relapsed/refractory mantle cell lymphoma: extended 3.5‐year
follow up from a pooled analysis. Haematologica. 2019;104(5):
e211‐e214.
SILKENSTEDT AND DREYLING
-
37
24. Martin P, Maddocks K, Leonard JP, et al. Postibrutinib outcomes
in patients with mantle cell lymphoma. Blood. 2016;127(12):
1559‐1563.
25. Wang M, Rule S, Zinzani PL, et al. Acalabrutinib in relapsed or re-
fractory mantle cell lymphoma (ACE‐LY‐004): a single‐arm, multi-
centre, phase 2 trial. Lancet. 2018;391(10121):659‐667.
26. Tam CS, Anderson MA, Pott C, et al. Ibrutinib plus Venetoclax for
the treatment of mantle‐cell lymphoma. N Engl J Med. 2018;378(13):
1211‐1223.
27. Ruan J, Martin P, Christos P, et al. Five‐year follow‐up of lenalido-
mide plus rituximab as initial treatment of mantle cell lymphoma.
Blood. 2018;132(19):2016‐2025.
28. Wang M, Munoz J, Goy A, et al. KTE‐X19 CAR T‐cell therapy in
relapsed or refractory mantle‐cell lymphoma. N Engl J Med. 2020;
382(14):1331‐1342.
How to cite this article: Silkenstedt E, Dreyling M. Mantle cell
lymphoma—Advances in molecular biology, prognostication
and treatment approaches. Hematological Oncology.
2021;39(S1):31–38. https://doi.org/10.1002/hon.2860
38
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SILKENSTEDT AND DREYLING
DOI: 10.1002/hon.2856
SUPPLEMENT ARTICLE
Personalized medicine for Hodgkin lymphoma: Mitigating
toxicity while preserving cure
Jemma Longley |Peter W. M. Johnson
Centre for Cancer Immunology, CRUK
Research Centre, University of Southampton,
Southampton, UK
Correspondence
Peter W. M. Johnson, Cancer Research UK
Centre, Southampton General Hospital,
Southampton SO16 6YD, UK.
Email: johnsonp@soton.ac.uk
Funding information
Cancer Research UK
Abstract
The treatment of classical Hodgkin lymphoma in young patients is one of the success
stories of modern medicine. The use of risk‐and response‐adapted approaches to
guide treatment decisions has led to impressive cure rates while reducing the long‐
term toxicity associated with more intensive therapies. Tissue biomarkers have not
yet proven more effective than clinical characteristics for risk stratification of patients
at presentation, but functional imaging features such as metabolic tumor volume may
be used to predict response, if early observations can be validated. The success of
treatment in younger patients has unfortunately not been mirrored in those over 60,
where complex decision‐making is often required, with a paucity of data from clinical
trials. The use of PD1 blocking antibodies and brentuximab vedotin in this cohort,
either alone or in combination with chemotherapy, may provide attractive options.
The incorporation of frailty assessment, quality‐of‐life outcomes, and specialist
geriatric input is also important to ensure the best outcomes for this diverse group.
KEYWORDS
antibody–drug conjugate, checkpoint blocking antibody, FDG‐PET, Hodgkin lymphoma
1
|
INTRODUCTION
Classical Hodgkin lymphoma (cHL) is a malignancy of germinal center
B cells, characterized by the presence of the Hodgkin Reed–
Sternberg (HRS) cell. It is the most common lymphoid malignancy
diagnosed in children and young adults in developed countries, with a
bimodal distribution peaking in the 2nd and 7th decades. Treatment
with radiotherapy, multimodality chemotherapy regimens, newer
antibody–drug conjugates, and immunotherapy checkpoint inhibitors
(ICI), using 2‐(
18
F)‐fluoro‐2‐deoxy‐D‐glucose (FDG) positron emis-
sion tomography (FDG‐PET) to direct therapy has translated into 10‐
year overall survival (OS) rates above 80%.
1
However, the ongoing
challenge remains of identifying patients with high‐risk disease who
will benefit the most from intensified therapy, while de‐escalating
treatment in those likely to be cured by less toxic regimens, to
minimize the long‐term morbidity and mortality seen in a minority of
survivors, without comprising outcomes. This article will outline the
emergence of new biomarkers to aid risk stratification and guide
treatment decisions at diagnosis, the use of different response‐
adapted approaches, and the incorporation of new targeted agents
in the treatment of both younger and older patients, in a more
personalized approach to therapy.
2
|
APPROACHES IN YOUNGER PATIENTS WITH
HODGKIN LYMPHOMA
The initial treatment of advanced‐stage HL with either bleomycin,
etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine
and prednisolone (escalated BEACOPP) or doxorubicin, vinblastine,
This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, pro-
vided the original work is properly cited.
© 2021 The Authors. Hematological Oncology published by John Wiley & Sons Ltd.
Hematological Oncology. 2021;39(S1):39–45. wileyonlinelibrary.com/journal/hon
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39
bleomycin, and dacarbazine (ABVD) is guided by risk stratification at
diagnosis, comorbidity, and patient preference. Excellent disease
control is achieved with more intensive BEACOPP regimens; how-
ever, this is at the price of increased acute toxicity and long‐term
morbidity, including second malignancies, infertility and cardiovas-
cular disease among survivors, when compared to less intensive
regimens. The use of six cycles of ABVD compared to four cycles of
escBEACOPP plus two cycles of standard BEACOPP in the Italian
HD2000 study showed no difference in 10‐year OS, despite a sig-
nificant difference in progression‐free survival (PFS) in favor of the
BEACOPP group at 5 years.
1
This is perhaps explained by the
significantly lower rates of second malignancy in patients treated
with ABVD had when compared to escBEACOPP (0.7% vs. 6.6%) and
the success of autologous stem cell transplant (ASCT) in the salvage
of relapsed disease. In the modern era, morbidity is predicted to be
lower as the number of BEACOPP cycles has been reduced using a
PET‐directed approach
2
; however, identification of patients with
higher risk disease at diagnosis seems important for choosing the
correct intensity of therapy, to optimize the chance of cure.
Risk stratification of patients' disease by the International Prog-
nostic Score (IPS) has previously been used to guide clinicians with
initial treatment decisions; however, compared to the dynamic
assessment of response by PET, it is less able to identify those pa-
tients with high‐risk disease that have a poorer outlook.
3
The incor-
poration of biologic features such as gene expression profiles in
addition to IPS has so far not yielded any prospectively validated
biomarkers, but measurement of metabolic tumor volume (MTV) and
total lesional glycolysis (TLG) at the baseline PET may provide a more
quantifiable assessment of tumor burden, a known predictor of poor
outcome.
4
The European collaborative group retrospectively
analyzed baseline total MTV (TMTV) in 258 patients with early‐stage
HL in the standard combined modality arm of the H10 trial and
showed that both TMVT and interim PET (iPET) following two cycles
of ABVD were independently prognostic of response to treatment,
and when combined, allowed identification of a high‐risk patient
group with a 5‐year PFS of only 25% (TMVT >148 cm
3
and iPET
positive—Deauville Score [DS] 4–5).
5
In this study, the TMTV was
calculated by summing all the extranodal and nodal lesions using the
41% maximum standardized uptake value threshold (SUVmax)
method. In advanced‐stage disease (stage IIB–IV), 848 patients
enrolled in the RATHL trial had baseline total/bulk MTV and TLG
measured using SUV ≥2.5 when compared to the liver (the 41%
SUVmax method was found not to be associated with PFS or 3‐year
HL events in this patient cohort).
6
Patients with a positive iPET
following two cycles of ABVD had a significantly higher total/bulk
MTV and TLG when compared to iPET‐negative patients (p=0.0002);
however, in a multivariate analysis, only total TLG, B symptoms, and
age were significantly associated with PFS. Patients with a negative
iPET and high‐volume TLG at baseline (defined as >3318 g) had a 5‐
year treatment failure rate of 31%, compared with 13.1% in low‐
volume TLG.
6
A study which retrospectively analyzed a total of 392
patients enrolled in both arms of the AHL 2011 LYSA trial identified a
small number of patients with a high‐baseline PET TMVT (set at a
threshold of 350 ml using the 41% SUVmax method) who had a
positive iPET (DS 4–5) following two cycles of escBEACOPP, with a 2‐
year PFS of 61% compared to 88% and 96% in patients with a low
TMTV/positive iPET and a low TMTV/negative iPET, respectively.
7
The rate of progression among patients with stage IV disease and a
negative iPET in the RATHL trial was 20% compared with less than
10% of patients enrolled in the GHSG H18 trial and LYSA study,
suggesting a more reliable negative predictive value of iPET after
more intensive regimens such as escalated BEACOPP in patients with
high‐risk disease.
3
Thus, baseline total MTV and TLG may prove
useful in the context of guiding initial intensity of treatment, by
identifying those at risk of treatment failure despite a negative iPET.
Measurement of total MTV/TLG will require standardization; how-
ever, similar to the Deauville scoring system that was developed for
iPET assessment to allow reproducibility and consistency when
stratifying patients into different risk groups and setting consistent
threshold values.
4
Prospective validation of this potential biomarker
in a large clinical trial is needed to ascertain its true prognostic value.
Patients with advanced‐stage HL and a positive iPET after two
cycles of ABVD in the RATHL trial went on to receive escalated
treatment with more intensive BEACOPP regimes (four cycles of
escBEACOPP or six cycles of BEACOPP‐14), with a 5‐year PFS of
65.7% and OS of 85.1%. This compares favorably to continuation of
ABVD following iPET in previous studies, where the PFS was consis-
tently less than 40%.
3
The South West Oncology Group (SWOG) 0816
trial showed at 5‐year follow‐up, 59 patients with advanced‐stage HL
(here defined as stage III–IV) and a positive iPET (DS 4–5) escalated to
escBEACOPP after two cycles of ABVD had a similar PFS of 66%, but
the rate of second malignancy was 14% with a short median onset of
4.2 years. In this study, six cycles of escBEACOPP were given
compared to four cycles in RATHL, which may partly explain the high
rate of secondary malignancy.
8
The GHSG H18 trial showed that pa-
tients with iPET‐positive disease following two cycles of escBEACOPP
who were treated with a total of six cycles of escBEACOPP had a
secondary malignancy rate of 9% at 5.5 years of follow‐up.
2
In the RATHL study, the treatment failed despite escalation to
BEACOPP regimens in 20 out of 37 patients with a DS of 5 on iPET,
and this group almost certainly requires a different approach to
improve their survival. The use of salvage therapy with high‐dose
chemotherapy (HDT) followed by ASCT is an option for patients
with initial chemorefractory disease, and was investigated by the
Italian HD0801 trial.
9
Here a positive iPET was defined as a DS of 3–
5, and therefore included a more favorable patient group when
compared to outcomes from RATHL and LYSA trials. Following two
cycles of ABVD, 81 (19%) patients remained iPET positive and
received HDT ASCT, with a 2‐year PFS of 75% suggesting that early
intensification might improve outcomes for this group.
9
The use of
newer agents such as brentuximab vedotin (BV) and anti‐PD1 anti-
bodies in the frontline treatment of patients with high‐risk iPET‐
positive disease may provide an alternative to ASCT, given their
activity in the relapsed/refractory disease; however, there is as yet
little data to support their use in a PET‐driven approach for this
selected group of patients. The Phase III ECHELON‐1 trial
40
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LONGLEY AND JOHNSON
incorporated six cycles of brentuximab with AVD chemotherapy
(A +AVD) and showed a 3‐year modified PFS (including a DS 3–5 at
the end of treatment as an event) of 83.1% compared with 76.2% in
patients' receiving six cycles of ABVD (7.1% difference p=0.005),
with a beneficial trend observed in iPET‐positive patients <60 years
receiving A+AVD (3‐year PFS 69.2% vs. 54.7%, respectively).
10
Therefore, A+AVD may be an attractive option for those patients
with high‐risk disease who wish to reduce the risk of long‐term
toxicity associated with BEACOPP regimes or who are unable to
tolerate escalation of therapy following a positive iPET.
In early stage unfavorable disease, the addition of BV to four
cycles of AVD within in a phase II PET‐directed pilot study in the
United States allowed the reduction of dose and intensity of radio-
therapy without apparently compromising treatment efficacy, with a
2‐year PFS of 97% among 29 patients who did not receive any
consolidation radiotherapy.
11
The phase III GHSG H17 trial in a
similar patient cohort also showed that the omission of radiotherapy
in those with a negative PET following two cycles of ABVD plus two
cycles of escBEACOPP was noninferior in terms of 5‐year PFS (2.2%
difference in favor of the radiotherapy group).
12
An initial high‐
intensity approach in the early‐stage disease thus appears to maxi-
mize cure rates without the need for consolidation radiotherapy in
those patients with a negative PET at the end of the treatment,
showing an improvement in the negative predictive value of iPET
when compared to the use of less intensive regimens.
The RATHL trial showed that the omission of bleomycin in patients
with a complete metabolic response at iPET did not compromise sur-
vival outcomes, and resulted in a lower incidence of pulmonary toxicity
(5‐year PFS and OS 84% and 98% vs. 86% and 97%, respectively).
3
Similarly in the AHL 2011 LYSA trial, 5‐year PFS was not significantly
different between patients treated with continued escBEACOPP or
de‐escalated to ABVD (86.2% standard arm vs. 85.7% PET‐driven arm)
leading to the conclusion that therapy can be reduced in those patients
whose disease responds to initial therapy without compromising sur-
vival outcomes.
13
The optimal number of escBEACOPP cycles was
investigated by the GHSG H18 trial in this context, and showed that in
patients with a negative iPET (DS 1–2) following two cycles of esc-
BEACOPP, the duration could be safely reduced to two further cycles,
with a small but statistically significant improvement in 5‐year survival
outcomes when compared to four cycles (PFS 92.2% vs. 90.8% OS 97.7
vs. 95.4%, respectively).
2
For patients with an IPS score of 1–2 and
favorable baseline characteristics, an initial two cycles of ABVD with
de‐escalation to AVD if iPET negative and escalation to four cycles of
escBEACOPP if iPET positive has a high probability of cure while
minimizing the number of patients exposed to the acute and long‐term
toxicity of BEACOPP regimes. The omission of radiotherapy in those
patients with a complete metabolic response did not affect survival
outcomes in the GHSG H15 study
14
and only 6.5% of patients received
consolidation radiotherapy without loss of disease control in the
RATHL trial.
3
There may be a role for radiotherapy in single‐site iPET‐
positive disease to reduce the number of patients escalated to more
intensive chemotherapy regimens; however, there is currently a lack of
prospective data supporting this approach.
3
|
IMMUNE CHECKPOINT INHIBITORS AND
EMERGING BIOMARKERS
The use of immune checkpoint inhibitors (ICI) in relapsed Hodgkin
lymphoma is well established, and the use of anti‐PD1 antibodies
combined with multi‐agent chemotherapy is being explored in the
first‐line setting. A study of affected nodes in those treated with anti‐
PD1 antibodies showed modification of the HL microenvironment in
response to anti‐PD1 therapy, with rapid depletion of HRS cells and a
reduction in PDL1‐expressing tumor‐associated macrophages and
regulatory T cells.
15
There was no clonal expansion and activation of
cytotoxic T cells as is seen in solid tumors, suggesting a mechanism of
action that is particular to HL, involving interruption of T cell–B cell
signaling pathways. Combination of nivolumab with AVD chemo-
therapy (N +AVD) for advanced‐stage HL (stage IIB–IV) was inves-
tigated by Ramchandren et al. who first gave nivolumab monotherapy
for 4 doses, followed by combination therapy (N +AVD) for 12 doses
every 2 weeks, with response assessment at the end of monotherapy,
after two combination cycles and at the end of the therapy.
16
Interestingly, at the end of monotherapy, the complete response rate
was 21%, with all patients in the highest quartile for expression of
PDL1 on HRS cells achieving a CR after combination therapy, main-
tained at 32 weeks of follow‐up. Discontinuation rates were low
(10%) with a febrile neutropenia rate of 10%. The most common
endocrine immune‐mediated adverse event (IMAE) was hypothy-
roidism, and the main nonendocrine IMAE was rash (grade 1–2).
Generally, the regimen was well tolerated, but there was one
treatment‐related death in an older patient, in CR after two cycles of
combination therapy who experienced four grade 3–4 adverse
events.
16
The use of pembrolizumab monotherapy prior to 4–6 cycles
of AVD in 30 patients with early unfavorable and advanced disease
showed an impressive 100% CR rate by the end of two cycles of AVD.
Responses were durable, with no progression or death at 22 months
of follow‐up, with no consolidation radiotherapy given at the end of
the treatment.
17
Phase III trial data comparing N +AVD versus
BV +AVD in the first‐line setting are awaited.
The pattern of disease response in the context of anti‐PD1
therapy has prompted revision of the Lugano Classification lym-
phoma response criteria, to include immunomodulatory therapy
(LYRIC), due to early imaging suggestive of progressive disease (PD)
in patients who later gained clinical benefit.
18
The phenomenon of
tumor flare or pseudo‐progression is well documented in patients
with solid tumors treated with ICI, as a result of immune cell infil-
tration or the delayed effect of these drugs allowing early tumor
growth. The use of early iPET to guide response‐adapted treatment
in HL may be particularly difficult to interpret in this context, with
the risk of tumor flare interpreted as a positive iPET and patients
subsequently escalated to more intensive regimes and exposed to
unnecessary toxicity whose disease may have responded at a later
time point. This resulted in the addition of indeterminate response
(IR) to CR PR and PD and allows the flexibility for patients to
continue treatment with further imaging at 12 weeks to confirm
either PD or response (Table 1). There may be a role for anti‐PD1
LONGLEY AND JOHNSON
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41
therapy in those patients with a DS of 5 on iPET as an alternative to
escalation of therapy to more intensive regimes, whose disease is
refractory to traditional chemotherapy.
4
|
APPROACHES FOR OLDER PATIENTS WITH
HODGKIN LYMPHOMA
The use of BV and ICI in the elderly may be an attractive option
as monotherapy, or in combination with less toxic chemotherapy
regimens, to improve the poorer survival outcomes when
compared to the younger population. The problems of comorbidity,
poor performance status (PS), increased adverse events, and low
tolerance of chemotherapy regimens at full dose in this hetero-
geneous population have resulted in the reported 3‐year PFS and
OS rates of 55% and 78%, respectively.
19
Evens et al. investigated
BV in sequential combination with AVD in 48 patients over 60
with untreated HL (stage II–IV) in a Phase II trial, which showed
encouraging 2‐year PFS and OS of 84% and 93%, respectively.
20
Patients were given two cycles of lead‐in and consolidation BV,
based on previous studies which have shown poor durability of
responses in older patients treated with BV monotherapy or BV
plus dacarbazine.
21
Only 52% of patients completed the full course
TABLE 1Lymphoma response to immunomodulatory therapy
criteria
IR criteria
IR1 Increase in overall tumor burden ≥50% of up to six measurable
lesions within the first 12 weeks of treatment without clinical
deterioration
IR2 Appearance of new lesions or increase in one or more existing
lesions ≥50% at any time during treatment in the context of
<50% increase in overall tumor burden
IR3 Increase in FDG update of ≥1 lesion(s) without an increase in size
or number of lesions
Abbreviations: FDG, fluoro‐2‐deoxy‐D‐glucose; IR, indeterminate
response.
TABLE 2List of instrumental activities of daily living
1 Planning, preparing and cooking a meal
2 Housekeeping and laundry
3 Ability to use the telephone
4 Managing finances
5 Shopping for personal items and food
6 Ability to drive or use public transportation
FIGURE 1 Flow charts of proposed treatment approaches for different presentations of Hodgkin lymphoma. Potential experimental
approaches for which the evidence is not yet mature are shown shaded
42
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LONGLEY AND JOHNSON
of therapy owing to side effects, but 75% of patients who
completed less than six cycles of AVD remained in CR at
2 years.
20
. Longer follow‐up is needed to ascertain if these re-
sponses are durable and to assess the long‐term cardiotoxicity
associated with receiving anthracycline chemotherapy in this pa-
tient cohort which included eight patients >80 years and 9 pa-
tients with a PS of 2.
The combination of N +AVD may prove to be a promising
strategy in fit older patients able to tolerate anthracycline
chemotherapy plus ICI therapy as initial treatment. The Phase II
trial by Ramachandren et al. detailed above included six patients
over 60, five of whom obtained a CR, while one died from toxicity
related to treatment.
16
Data from a larger Phase II trial combining
nivolumab with AVD in older patients with high‐risk disease (IPS
score ≥3) and a positive iPET (DS 4–5) are awaited
(NCT03033914) to assess the activity and safety of this regimen in
a larger cohort of patients.
A chemotherapy‐free approach in older patients is an attrac-
tive one in those with poor performance status. A Phase II study
combining nivolumab and BV (N +BV) in elderly patients with a
PS of 0–1 by Yasenchak et al. showed a CR rate of 72% following
16 cycles of treatment that was well tolerated.
22
A subsequent
interim analysis of a similar phase II trial which included a patient
population with poorer PS (0–2) showed a more modest ORR of
61% with CR of 48% following eight cycles of treatment, which
unfortunately did not meet the predefined ORR of 68% and was
therefore terminated early.
23
The frequency of adverse events was
reduced compared to the smaller trial (26% vs. 37% sensory
neuropathy [all grades], respectively) which may be explained by
the difference in the number of cycles received. The strategies to
reduce the number of treatment cycles without compromising
survival should be explored in future, to minimize toxicity and
allow the majority of patients to complete therapy with minimal
dose reductions and treatment interruptions.
The use of comprehensive geriatric assessment (GCA) and quality‐
of‐life (QOL) outcomes in older patients are recommended, but data on
their feasibility are lacking in the prospective clinical trial setting.
Evens et al. used the Cumulative Illness Geriatric (CIRS‐G)
FIGURE 1 (Continued)
LONGLEY AND JOHNSON
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43
comorbidity score (https://www.mdcalc.com/cumulative‐illness‐rat-
ing‐scale‐geriatric‐cirs‐g) to stratify patients into high or low groups at
diagnosis (CIRS‐G score cut‐off 10); however, in a multivariable anal-
ysis, this was not significant in predicting PFS, while the loss of
instrumental activities of daily living (IADLs) were predictive of both
OS and PFS, with 2‐year PFS of 94% versus 25% in patients with no
IADL loss versus IADL loss and 2‐year OS of 97% versus 67%,
respectively.
20
This assessment is quick and convenient for the busy
oncologist to use in the clinic, to inform the initial treatment decisions,
and help tailor initial therapy to each individual patient's circum-
stances (Table 2).
5
|
CONCLUSIONS
The use of PET‐directed therapy in younger patients with advanced
HL has allowed safe de‐escalation of treatment for those with
responsive disease at iPET, sparing the acute and long‐term toxicity
of more intensive chemotherapy regimens and consolidation radio-
therapy. Figure 1summarises the approaches currently in use, and
some of the areas of emerging evidence for new treatments. Further
information regarding high‐risk features at diagnosis in the PET‐
directed era is required, however, and measurement of baseline
PET characteristics may prove a valuable predictive biomarker. The
use of ICI therapy as part of initial therapy, guided by prospective
trials incorporating biomarkers related to the tumor microenviron-
ment is awaited, although the use of PET‐directed therapy in this
context is likely to be more complex, with the phenomenon of tumor
flare and delayed response making interpretation harder. The use of
BV and ICIs in older patients appears promising; however, prospec-
tive incorporation of geriatric and QOL assessment into clinical trials
is currently lacking. The use of IADL assessment may provide on-
cologists with a tool to quickly assess patients in the clinic and help
with decision‐making in this complex patient population.
ACKNOWLEDGMENT
Both authors are supported by grants from Cancer Research UK.
CONFLICT OF INTEREST
Dr. Longley: no conflicts; Dr. Johnson: Research funding from Jans-
sen, Epizyme; Consulting fees from Takeda, Bristol‐Myers Squibb,
Novartis, Genmab, Incyte, Morphosys, and Kymera.
ORCID
Peter W. M. Johnson https://orcid.org/0000-0003-2306-4974
REFERENCES
1. Merli F, Luminari S, Gobbi PG, et al. Long‐term results of the
HD2000 trial comparing ABVD versus BEACOPP versus COPP‐
EBV‐CAD in untreated patients with advanced Hodgkin lym-
phoma: a study by Fondazione Italiana Linfomi. J Clin Oncol.
2016;34(11):1175‐1181.
2. Borchmann P, Goergen H, Kobe C, et al. PET‐guided treatment in
patients with advanced‐stage Hodgkin's lymphoma (HD18): final
results of an open‐label, international, randomised phase 3 trial by
the German Hodgkin study group. Lancet. 2018;390(10114):2790‐
2802.
3. Johnson P, Federico M, Kirkwood A, et al. Adapted treatment guided
by interim PET‐CT scan in advanced Hodgkin's lymphoma. N Engl J
Med. 2016;374(25):2419‐2429.
4. Trotman J, Barrington SF. The role of PET in first‐line treatment of
Hodgkin lymphoma. Lancet Haematol. 2021;8(1):e67‐e79.
5. Cottereau A‐S, Versari A, Loft A, et al. Prognostic value of baseline
metabolic tumor volume in early‐stage Hodgkin lymphoma in the
standard arm of the H10 trial. Blood. 2018;131(13):1456‐1463.
6. Pike LC, Kirkwood AA, Patrick P, et al. Can baseline PET‐CT features
predict outcomes IN advanced Hodgkin lymphoma? A prospective
evaluation OF UK patients in the RATHL trial (CRUK/07/033).
Hematol Oncol. 2017;35(S2):37‐38.
7. Casasnovas R‐O, Kanoun S, Tal I, et al. Baseline total metabolic
volume (TMTV) to predict the outcome of patients with advanced
Hodgkin lymphoma (HL) enrolled in the AHL2011 LYSA trial. J Clin
Oncol. 2016;34(15_suppl):7509.
8. Stephens DM, Li H, Schöder H, et al. Five‐year follow‐up of
SWOG S0816: limitations and values of a PET‐adapted approach
with stage III/IV Hodgkin lymphoma. Blood. 2019;134(15):1238‐
1246.
9. Zinzani PL, Broccoli A, Gioia DM, et al. Interim positron emission
tomography response‐adapted therapy in advanced‐stage Hodgkin
lymphoma: final results of the phase II part of the HD0801 study. J
clin oncol. 2016;34(12):1376‐1385.
10. Straus DJ, Długosz‐Danecka M, Alekseev S, et al. Brentuximab
vedotin with chemotherapy for stage III/IV classical Hodgkin lym-
phoma: 3‐year update of the ECHELON‐1 study. Blood.
2020;135(10):735‐742.
11. Kumar A, Casulo C, Advani RH, et al. A pilot study of brentuximab
vedotin combined with AVD chemotherapy and radiotherapy in
patients with newly diagnosed early stage, unfavorable risk Hodgkin
lymphoma. Blood. 2019;134(Suppl_1):2834.
12. Borchmann P, Plütschow A, Kobe C, et al. PET‐guided omission of
radiotherapy in early‐stage unfavourable Hodgkin lymphoma (GHSG
HD17): a multicentre, open‐label, randomised, phase 3 trial. Lancet
Oncol. 2021;22(2):223‐234.
13. Casasnovas R‐O, Bouabdallah R, Brice P, et al. PET‐adapted treat-
ment for newly diagnosed advanced Hodgkin lymphoma (AHL2011):
a randomised, multicentre, non‐inferiority, phase 3 study. Lancet
Oncol. 2019;20(2):202‐215.
14. Engert A, Haverkamp H, Kobe C, et al. Reduced‐intensity
chemotherapy and PET‐guided radiotherapy in patients with
advanced stage Hodgkin's lymphoma (HD15 trial): a randomised,
open‐label, phase 3 non‐inferiority trial. Lancet. 2012;379(9828):
1791‐1799.
15. Reinke S, Bröckelmann PJ, Iaccarino I, et al. Tumor and microenvi-
ronment response but no cytotoxic T‐cell activation in classic
Hodgkin lymphoma treated with anti‐PD1. Blood. 2020;136(25):
2851‐2863.
16. Ramchandren R, Domingo‐Domènech E, Rueda A, et al. Nivolumab
for newly diagnosed advanced‐stage classic Hodgkin lymphoma:
safety and efficacy in the phase II CheckMate 205 study. J Clin Oncol.
2019;37(23):1997‐2007.
17. Allen PB, Savas H, Evens AM, et al. Pembrolizumab followed by AVD
in untreated early unfavorable and advanced stage classical Hodgkin
lymphoma. Blood. 2020;137(10):1318‐1326.
18. Cheson BD, Ansell S, Schwartz L, et al. Refinement of the Lugano
Classification lymphoma response criteria in the era of immuno-
modulatory therapy. Blood. 2016;128(21):2489‐2496.
19. Evens AM, Sweetenham JW, Horning SJ. Hodgkin lymphoma in older
patients: an uncommon disease in need of study. Oncology.
2008;22(12):1369‐1379.
44
-
LONGLEY AND JOHNSON
20. Evens AM, Advani RH, Helenowski IB, et al. Multicenter phase II
study of sequential brentuximab vedotin and Doxorubicin, vinblas-
tine, and dacarbazine chemotherapy for older patients with un-
treated classical Hodgkin lymphoma. J Clin Oncol. 2018;36(30):3015‐
3022.
21. Friedberg JW, Forero‐Torres A, Bordoni RE, et al. Frontline bren-
tuximab vedotin in combination with dacarbazine or benda-
mustine in patients aged ≥60 years with HL. Blood. 2017;130(26):
2829‐2837.
22. Yasenchak CA, Bordoni R, Yazbeck V, et al. Phase 2 study of
frontline brentuximab vedotin plus Nivolumab in patients with
Hodgkin lymphoma aged ≥60 years. Blood. 2019;134(Suppl_1):237.
23. Cheson BD, Bartlett NL, LaPlant B, et al. Brentuximab vedotin plus
nivolumab as first‐line therapy in older or chemotherapy‐ineligible
patients with Hodgkin lymphoma (ACCRU): a multicentre, single‐
arm, phase 2 trial. Lancet Haematol. 2020;7(11):e808‐e815.
How to cite this article: Longley J, Johnson PWM.
Personalized medicine for Hodgkin lymphoma: Mitigating
toxicity while preserving cure. Hematological Oncology.
2021;39(S1):39–45. https://doi.org/10.1002/hon.2856
LONGLEY AND JOHNSON
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45
Received: 17 February 2021
DOI: 10.1002/hon.2850
SUPPLEMENT ARTICLE
Cutaneous T‐cell lymphomas—An update 2021
Werner Kempf
1,2
|Christina Mitteldorf
3
1
Kempf und Pfaltz Histologische Diagnostik,
Zurich, Switzerland
2
Department of Dermatology, University
Hospital Zurich, Zurich, Switzerland
3
Department of Dermatology, Venereology
and Allergology, University Medical Center
Göttingen, Göttingen, Germany
Correspondence
Werner Kempf, Department of Dermatology,
University Hospital Zurich, Zurich CH‐8091,
Switzerland.
Email: werner.kempf@uzh.ch
Abstract
Cutaneous T‐cell lymphomas (CTCL) represent the majority of primary cutaneous
lymphomas (CL). Mycosis fungoides (MF) and cutaneous CD30+lymphoprolifer-
ative disorders account for 80% of all CTCL. CTCL show overlapping histological
features. Thus clinical‐pathological correlation is of importance to achieve final
diagnosis. MF shows a characteristic evolution with patches, plaques, and in a
subset of patients (10%–20%) with tumors. Therapy is stage‐adapted with skin‐
directed therapies such as UV‐light therapies and corticosteroids in early disease
stage (i.e., patch and limited plaque stage) and systemic therapies (retinoids, inter-
feron, mono chemotherapy, targeted therapy) and/or radiation therapy (local or
total skin beam electron) in advanced stages. Novel therapies include targeted
therapy such as mogamulizumab (anti‐CCR4) or brentuximab vedotin (anti‐CD30)
and histone deacetylase inhibitors. Considering the impact of targeted therapies,
biomarkers such as CD30 are not only crucial for the diagnosis and correct classi-
fication of an individual lymphoma case, but also for therapy as they may represent
therapeutic targets. In the recently revised WHO classification 2017 and the
updated WHO‐EORTC classification for CL 2018, primary cutaneous CD8+acral T‐
cell lymphoma has been introduced as a new still provisional entity. It displays
characteristic clinical, histological, and phenotypic features and exhibits an excellent
prognosis. Rare, but aggressive CTCL include cutaneous primary cutaneous
aggressive epidermotropic CD8‐positive T‐cell lymphoma and cutaneous gamma/
delta T‐cell lymphoma, which present with rapid onset of necrotic or ulcerated
plaques and tumors. As they have a poor prognosis, treatment includes multiagent
chemotherapy and hematopoietic stem cell transplantation.
KEYWORDS
classification, cutaneous, dermatopathology, diagnosis, lymphoma, skin, T‐cell, therapy
1
|
INTRODUCTION
The group of primary cutaneous lymphomas (CL) are the second most
common group of extranodal lymphomas. Among CL, cutaneous T‐
cell lymphomas (CTCL) represent the majority accounting for
approximately 65%–75% of all CL.
1
All other CTCL forms are rare
with each entity accounting for less than 1% of all CTCL. Primary CL
present in the skin without extracutaneous disease at the time of
diagnosis and often remain limited to the skin over long periods of
disease evolution. Progression with extracutaneous spread occurs
usually in advanced late stages.
CTCL exhibit a wide spectrum of clinical, histological, immuno-
phenotypic features and genetic alterations. As these histological and
phenotypic features overlap within the various forms of CTCL, cor-
relation of the clinical features with the histological and immuno-
phenotypic findings is an essential element of the diagnostic work‐up
46
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Hematological Oncology. 2021;39(S1):46–51. wileyonlinelibrary.com/journal/hon © 2021 John Wiley & Sons Ltd.
and implies that clinical images and dermatologic examination are
indispensable to achieve the final diagnosis. The prognosis and
treatment significantly differ among the entities within the CTCL
group and also from systemic lymphomas with similar histological
features.
Recent developments such as targeted therapy have expanded
the therapeutic spectrum in CTCL and contribute to a significant
change in the prognosis, particularly in advanced forms of several
CTCL forms. The therapeutic response to a distinct targeted therapy,
however, varies among different CTCL entities. The exact classifica-
tion of CTCL entities is important to compare results of clinical trials
and to assess the value of targeted therapy. CTCL without further
specification should not be used as a diagnostic term in therapeutic
trials as this designation does not allow to identify differences in the
responses to therapy among the distinct CTCL forms. The classifi-
cation and terminology of CL should follow the current revised WHO
classification 2017 (Table 1) and the updated WHO‐EORTC classifi-
cation for CL 2018.
1,2
An example for the efficacy of targeted therapy in CTCL is
brentuximab vedotin (BV), which targets CD30 expressed on
tumor cells. It is not only a new and efficient treatment for
relapsed or therapy refractory CD30 lymphoproliferative disor-
ders (LPDs) such as multifocal primary cutaneous anaplastic large
cell lymphoma (PC‐ALCL) but also expanded the therapeutic
strategies for advanced mycosis fungoides (MF) and Sézary
syndrome.
3
Moreover, BV was even effective in some patients in
whom rare and aggressive CTCL forms such as cutaneous
gamma/delta T‐cell lymphoma showed exceptional expression of
CD30.
Considering the impact of targeted therapies, biomarkers such as
CD30 are not only crucial for the diagnosis and correct classification
of an individual lymphoma case, but also for therapy as they may
represent therapeutic targets. In consequence, the detection of
biomarker expression by immunohistochemistry or other in situ
techniques became an important aspect in the diagnostic work‐up of
CTCL. Inter‐observer variability and differences in the technical as-
pects, however, are critical factors in the assessment of biomarkers.
Thus, detection methods and expression level need to be standard-
ized especially in situations, in which the expression level of a target
is decisive for the selection of therapy. Digital image analysis tools
are currently developed for the automatized evaluation of immuno-
histochemical slides with the aim to reduce the interinstitutional and
interrater variability. Nevertheless, the results should always be
interpreted in a synoptic way taking into account the context of
clinical and histopathological context, especially since CD30 expres-
sion is found in a broad range of CTCL.
4
2
|
CTCL ENTITIES
MF is the most common form of CTCL and accounts for nearly
50% of all primary CL.
1
MF shows a characteristic disease evo-
lution with erythematous patches (patch stage) which may evolve
into more infiltrated plaques (plaque stage). The patches and
TABLE 1Spectrum of primary
cutaneous T‐cell lymphomas according
to revised WHO classification of
hematopoietic tumors (2017) and the
updated WHO‐EORTC classification for
primary cutaneous lymphomas (2018)
Mycosis fungoides (MF)
MF variants
�Folliculotropic MF
�Granulomatous slack skin
�Pagetoid reticulosis
Sézary syndrome
Adult T‐cell leukemia/lymphoma
Primary cutaneous CD30‐positive lymphoproliferative disorders
�Lymphomatoid papulosis
�Primary cutaneous anaplastic large cell lymphoma
Subcutaneous panniculitis‐like T‐cell lymphoma
Primary cutaneous gamma/delta T‐cell lymphoma
Primary cutaneous aggressive epidermotropic CD8‐positive T‐cell lymphoma (provisional)
Primary cutaneous CD4+small/medium‐sized pleomorphic T‐cell lymphoproliferative disorder
(provisional)
Primary cutaneous acral CD8+T‐cell lymphoma (provisional)
Primary cutaneous peripheral T‐cell lymphoma, not otherwise specified (NOS)
Extranodal NK/T‐cell lymphoma, nasal type
Hydroa vacciniforme‐like lymphoproliferative disorder
Abbreviation: MF, mycosis fungoides.
KEMPF AND MITTELDORF
-
47
plaques usually persist over long time, that is, months or years. In
a subset of patients, large and often ulcerated tumors (tumor
stage) develop.
As the histological findings may be subtle especially in patch
stage of MF, distinction from benign inflammatory skin diseases
such as chronic eczema may not always be possible at this disease
stage and require repeated biopsies from different lesions. This may
also explain the delay of several months to years in the diagnosis of
early MF.
Enlarged lymph nodes with clinical and/or radiologic suspicion
for lymphoma involvement should be either biopsied. Bone marrow
biopsy is only indicated in advanced disease stage or if circulating
atypical lymphocytes in the peripheral blood are present.
Histologic work‐up is not only important to identify MF and to
distinguish MF from inflammatory skin diseases, but it also allows to
identify variants and subtypes of MF which may differ in their course
from classic MF. Folliculotropic MF (FMF) is a distinct variant of MF
accounting for approximately 10% of all MF cases and characterized
by folliculotropic infiltrates, that is, exocytosis of tumor cells into the
hair follicle epithelia resulting in alopecic patches and plaques.
5
Recently, two prognostic subsets of FMF could be identified. The
early form of FMF manifests with follicular papules, acneiform lesions
with comedones and cysts and histologically with subtle lymphocytic
infiltrates. The advanced form of FMF is characterized by more
extensively infiltrated thicker alopecic plaques and deep, dense
lymphocytic infiltrates. The course and prognosis of advanced form is
similar to tumor stage of MF, whereas the early form displays the
same indolent course as the classic form of MF (patch stage).
The prognosis in the patch and limited plaque stage is favorable
with 5‐and 10‐year survival rates over 90% reflecting the slowly
progressive and indolent course of the disease in most patients. In
stage IB the 10‐year‐survival rate is 80% but drops to 40% in stage
IIB.
6
whereas the prognosis in the patch and limited plaque stage is
favorable. MF in tumor stage is aggressive and associated with the
risk for extracutaneous spread which often first involves lymph
nodes. During disease progression, visceral or other organs may
become involved and sepsis originating from bacterial colonization of
ulcerated tumors. Remarkably, the majority of patients (80%) will not
progress to tumor stage. Thus, it is important to emphasize this point
in counseling MF patients as they will get often terrified when
looking to images of advanced MF seen during their Internet
searches to retrieve more information about the disease and the
treatment modalities.
Treatment of MF is stage‐adapted which is also reflected in in-
ternational and national guidelines (Table 2).
Skin‐directed therapies (UV light, topical corticosteroids, nitro-
gen mustard) are the main strategies for early stage of MF and sys-
temic therapies (retinoids, chemotherapy, targeted therapy) for
advanced disease (extensive plaque and tumor stage).
7,8
It should be noted that in selected patients with stage IA (limited
patch stage) a watch‐and‐wait strategy may be justified. In early MF
(patch and limited plaque stage), skin‐directed therapies comprise
treatment by UV‐light (UVB narrow band, psoralen UVA [PUVA]),
topical corticosteroids (CS) and the newly introduced topical mech-
lorethamine (nitrogen mustard) representing a topically applied
cytotoxic agent. Topical CS and UV‐light approaches result in com-
plete clinical response in up to 60% and 80%–90% of the patients,
respectively. These therapies should be intermittently applied to
prevent or reduce the long‐term complications of UV‐light treatment
(epithelial skin cancers) and toxicity of potent topical corticosteroids
(skin atrophy and fragility). Topical mechlorethamine (nitrogen
mustard) represents a novel therapy for MF in patch and limited
plaque stage with response rates up to 60% of the patients and
represents an alternative, but more cost‐intense treatment for pa-
tients not responding to other skin‐directed therapies. Irritative and
allergic dermatitis are seen as adverse effects.
In patients with relapses or therapy refractory course and
development of plaques, skin‐directed treatment is combined with
systemic treatment including retinoids and retinoid analogues (aci-
tretin; bexarotene) or low‐dose methotrexate. Interferon‐alpha (IFN),
which was an effective alternative to retinoids and reached response
TABLE 2Treatment of MF
Topical therapies:
Corticosteroids ointments
Bexarotene gel (US)
Chlormethine gel
UV‐light therapies:
UVB narrow band (if patches only)
PUVA (alone or in combination with other therapies)
Systemic therapies:
Interferon alpha
a
Oral bexarotene
Mogamulizumab (anti‐CCR4)
Brentuximab vedotin (anti‐CD30 coupled with monomethyl
auristatin E)
Histon deacetylase inhibitors
Chemotherapy:
Methotrexate (low dose) or pralatrexate (US)
Gemcitabine (low‐dose)
Pegylated liposomal doxorubicin
CHOP (extracutaneous spread)
Radiotherapy:
Local radiotherapy (solitary or few tumors)
Total skin electron beam (generalized thick plaques and tumors).
Extracorporeal photopheresis (erythrodermic MF)
Allogeneic hematopoietic stem cell transplantation
Abbreviation: MF, mycosis fungoides.
a
Production of non‐pegylated INF alpha 2a stopped, alternatively
pegylated interferon alpha (limitation: not approved for MF).
48
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KEMPF AND MITTELDORF
rates of more than 50% in combination with PUVA, is not any longer
produced. The non‐pegylated INF alpha is not any longer available,
but pegylated INF alpha might be an alternative. Similar response
rates can be achieved by the combination of PUVA and retinoids
(acitretin or bexarotene).
As an alternative to systemic retinoids, topical retinoids such as
alitretinoin, bexarotene, and tazarotene can be used. As in mechlor-
ethamine, irritation is a common adverse effect. In patients with
single tumors in otherwise patch and plaque stage, local radiotherapy
for tumors is effective.
Recently, new treatment options became available such as moga-
mulizumab, a humanized antibody against CCR4 (CC‐chemokine
receptor 4) as targeted therapy which leads to a prolonged
progression‐free survival. Histone deacetylase inhibitors (HDACi),
such as vorinostat, romidepsin, and resminostat, interact with various
pathways involved in tumor cell growth. Clinical response to HDACi
therapy is observed in approximately one‐third of patients. Resmino-
stat is tested in clinical trials as a maintenance therapy and seems to
enhance response to other therapies.
In more advanced disease (thick plaques, tumor stage), mono-
chemotherapy with gemcitabine or pegylated liposomal doxorubicin
are effective. CHOP‐based chemotherapy regimens should be
restricted to patients with extracutaneous spread and usually result
in only short‐lived response. Moreover, they seem to increase the
risk for sepsis. Neoplastic cells in MF tumors may express CD30
which renders them to candidates for a targeted therapy with BV, an
anti‐CD30‐based antibody conjugated to monomethyl auristatin E as
a cytostatic drug. In cases with more than 5% of the tumor cells
expressing CD30, clinical response to BV was observed and could
induce regression of even large, ulcerated tumors. Alternatively, total
body skin electron beam irradiation is effective for patients with
multiple MF tumors. This treatment modality is, however, only
available in certain centers. Allogeneic hematopoietic stem cell
transplantation is a potentially curative treatment option and is
effective in up to 60% of patients with advanced MF and Sézary
syndrome but is limited by the high relapse rate and the high mor-
tality associated with this therapy.
9
Primary refractory disease,
relapse, or progression in patients that had received three systemic
treatments prior to transplant were identified as independent
adverse prognostic factors. Pretreatment with total skin electron
beam therapy may be beneficial before stem cell transplantation.
7
Bacterial toxins, especially those of Staphylococcus aureus, are
able to activate STAT3 and stimulate proliferation of tumor cells, and
suppress the activity of tumor‐infiltrating CD8+cells against the
tumor cells. Antibiotic treatment resulted in clinical improvement in
MF as well as in Sézary syndrome.
10
Sézary syndrome (SES) is an aggressive form of CTCL, which is
derived from central memory T‐cells. Clinically, SES manifests with
generalized skin involvement with erythroderma accompanied by
intense pruritus, enlarged lymph nodes (with or without specific
involvement by the neoplastic cells), and a leukemic spread of tumor
clone. Diagnosis requires demonstration of the same tumor clone in
the skin lesions and the peripheral blood as well as additional he-
matologic findings (absolute Sézary cell count of >1000 cells/µl or an
expanded CD4+T‐cell population leading to a CD4/CD8 ratio ≥10,
CD4+/CD7‐cells ≥40% or CD4+/CD26‐cells ≥30%). Histological
diagnosis may be challenging as nonspecific findings are common.
Immunohistochemical (bio‐)markers such as PD‐1, TOX, CD7,
KIRDL2, and the proliferation rate were shown to be useful markers
in the histopathological diagnosis of SES and the distinction from
benign inflammatory erythrodermic skin diseases such as atopic
dermatitis or drug eruption.
11
Other T‐cell non‐Hodgkin lymphomas
present with a leukemic phase and may involve the skin such as T‐cell
large granular lymphocytosis (T‐LGL), T‐cell prolymphocytic leukemia
(T‐PLL), and adult T‐cell lymphoma/leukemia (ATLL). The tumor cells
in T‐LGL are large with abundant cytoplasm and azurophilic granula.
In contrast to SES, the course of T‐LGL is usually indolent. Expression
of TCL‐1 detected by immunohistochemistry or flow cytometry is
helpful in the diagnosis of T‐PLL. ATLL is linked to human T‐cell
lymphotropic virus 1 which differs from SES, T‐LGL, and T‐PLL.
Treatment of SES includes extracorporeal photopheresis (ECP) with a
wide range of response rates up to 80% and complete response rates
up to 25%.
7
ECP is often combined with systemic therapies used in
MF, for example, bexarotene. Alemtuzumab and chemotherapy
(gemcitabine, pegylated liposomal doxorubicin) are used as second‐
line treatment. Recently mogamulizumab was reported as an effec-
tive treatment in SES.
Primary cutaneous CD30‐positive lymphoproliferative disorders
(CD30+LPD) are the second most common group of CTCL (25% of all
CTCL) and include PC‐ALCL, lymphomatoid papulosis (LYP) and
borderline lesions.
4,12
CD30+LPD exhibit an indolent course with a
good prognosis despite recurrences are frequent. PC‐ALCL manifests
with a solitary or grouped, rapidly growing, and often ulcerated large
tumor(s). Histologically, dense cohesive infiltrates of predominantly
large pleomorphic or anaplastic tumor cells which express CD30 and
show a variable loss of T‐cell markers. PC‐ALCL does not have a
t(2;5) and thus is negative for anaplastic lymphoma kinase (ALK).
Rearrangements of the DUSP22‐IRF4 locus are found in approxi-
mately 25‐30% of PC‐ALCL and rearrangements of TP63 are very
rare in PC‐ALCL. In contrast to systemic ALCL, DUSP22‐IRF4 rear-
rangemnt does not have a prognostic impact in PC‐ALCL. CD30
expression is not restricted to CD30+LPD, in which the vast majority
of tumor cells express this marker. Therefore, other CTCL such as
MF, particular in tumor stage, need to be distinguished from PC‐
ALCL and LYP by correlation of the histological findings with clinical
presentation to achieve correct diagnosis within the group of CTCL.
Despite relapses are common, PC‐ALCL has a favorable prognosis
with 5‐year survival rate of 90%. Patients with extensive limb disease
and multifocal PC‐ALCL are at risk to develop extracutaneous spread
and show impaired prognosis.
Surgical excision or radiation therapy is the first‐line treatment
for solitary or localized PC‐ALCL. For patients with multifocal lesions,
low‐dose methotrexate (MTX; up to 25 mg/kg per week) or local
radiotherapy in case of only a few lesions is recommended. BV is an
KEMPF AND MITTELDORF
-
49
effective treatment with high response rates in patients who do not
respond to MTX or develop extracutaneous spread to locoregional
lymph nodes.
3,8
Multiagent chemotherapy is indicated only in pa-
tients with extracutaneous spread to visceral organs or CNS or lack
of response to BV.
LYP presents with grouped or generalized papules and small
nodules which show the characteristic spontaneous regression of the
individual lesions within a few weeks. Histology shows a broad
spectrum with five different subtypes (referred to as type A–E) and a
subtype with chromosomal rearrangements involving the DUSP‐IRF4
locus on 6p25.3 listed in the revised WHO and updated WHO‐
EORTC classification.
1,2,4
Some of these histological types pose
diagnostic difficulties as they simulate aggressive CTCL (e.g., type D
and E). Thus clinical‐pathological correlation is crucial for the diag-
nosis as LYP displays overlapping histological features with other
CTCL forms. LYP carries an excellent prognosis with 5 and 10‐year‐
survival rate of almost 100%. Nevertheless, LYP patients are at risk
to develop a second lymphoma, especially MF and cutaneous or nodal
ALCL which occurs in 15% of the patients.
In regard to the excellent prognosis, a watch‐and‐wait strategy
for LYP can be justified. UV‐light (UVB narrow band or PUVA) and
low‐dose methotrexate (5–20 mg per week) are the most common
therapies, but relapses after withdrawal of treatment are common.
13
Thus, the effects of these therapies need to be balanced against long‐
term adverse effects. For patients with disseminated lesions and lack
of response to MTX or UV‐light therapies, BV represents a new
therapeutic strategy and has been used with lower dose than in other
CD30+T‐cell lymphomas. For larger lesions (i.e., 2–3 cm in diameter)
which do not regress within 3 months, surgical excision or local
radiotherapy can be applied.
Subcutaneous panniculitis‐like T‐cell lymphoma (SPTCL) is a cyto-
toxic T‐cell lymphoma defined by infiltrates of mostly CD8+pleo-
morphic lymphocytes in the lobuli of subcutaneous fat tissue.
1,2
The
neoplastic cells express TCR alpha/beta which distinguishes them
from expression of TCR gamma/delta by the tumor cells in the sub-
cutaneous form of gamma/delta T‐cell lymphoma. SPTCL may affect
children as well as adults and presents with subcutaneous plaques or
nodules which involve preferentially the extremities. Regression of
lesions results in focal lipatrophy. In addition to the skin lesions,
systemic symptoms including fever, fatigue and weight loss, cytope-
nia, and elevated liver enzymes can be present. Some patients suffer
from systemic lupus erythematosus. There are overlapping features
between lupus panniculitis to SPTCL.
In most patients, SPTCL shows an indolent course with a favor-
able prognosis (5‐year‐SR: 80%).
1
In 15% of the patients, SPCTL is
complicated by hemophagocytic lymphohistiocytosis (HLH), which is
linked to an aggressive course with high mortality. Recently, germline
mutations in HAVCR2 were found in 60% of SPTCL which result in
loss of function or missense variants of T‐cell immunoglobulin mucin
3 as a modulator of immune responses expressed on subgroups of T
and innate immune cells.
14
This results in persistent immune
activation and increased production of inflammatory cytokines which
promote HLH and SPTCL. The hyperactive immune reaction in SPTCL
may explain the fact that immunosuppressive therapies are effective
in these patients. Immunosuppressive drugs such as steroids, MTX,
and cyclosporine have replaced chemotherapy as first‐line therapy
for SPTCL, independent of the presence of HLH.
8
CD8+acral T‐cell lymphoma (CD8+ATCL) is a new provisional
CTCL entity introduced for the first time in the revised WHO clas-
sification 2017 and updated WHO‐EORTC classification 2018.
1,2
This
lymphoproliferation manifests with a solitary or rarely bilateral
nodule(s) at acral sites, that is, ears, face, and feet. Histology is
characteristic and shows a dense dermal infiltrate of small to me-
dium‐sized atypical lymphocytes with moderate nuclear atypia.
15
There is no epidermotropism of neoplastic cells in CD8+ATCL which
differs from the epidermotropic infiltrates in CD8+MF and CD8+
AECTCL. The tumor cells in CD8+ACTL exhibit a characteristic
phenotype with expression of CD3+, CD8+, and TIA‐1+in the
absence of other cytotoxic markers such as granzyme B and perforin.
In the CD68 stain, a characteristic perinuclear dot‐like pattern is
observed. The course is indolent with an excellent prognosis. Staging
is not necessary in cases with typical clinical presentation and his-
tology. CD8+ACTL can be treated with surgical excision or
radiotherapy.
3
|
CONCLUSIONS
CTCL are characterized by distinct clinical features but show signif-
icant overlap in histological and phenotypic features. Thus clinical‐
pathologic correlation is of outmost importance in the diagnostic
work‐up of CTCL. MF and cutaneous CD30+LPD represent the most
common form of CTCL. The therapeutic approach for MF depends on
disease stage and evolution. CD30 LPD exhibit a favorable prognosis.
Therefore, unnecessary aggressive treatment should be avoided.
Targeted therapy are novel and effective treatment modalities for
advanced MF and in patients with therapy refractory CD30 LPD.
CONFLICT OF INTEREST
The authors have no conflict of interest to declare.
PEER REVIEW
The peer review history for this article is available at https://publons.
com/publon/10.1002/hon.2850
ORCID
Werner Kempf https://orcid.org/0000-0002-6552-8629
REFERENCES
1. Willemze R, Cerroni L, Kempf W, et al. The 2018 update of the
WHO‐EORTC classification for primary cutaneous lymphomas.
Blood. 2019;133(16):1703‐1714.
50
-
KEMPF AND MITTELDORF
2. Swerdlow SH, Campo E, Harris NL, et al. WHO Classification of Tu-
mours of Haematopoietic and Lymphoid Tissues. Lyon: IARC; 2017.
3. Engelina S, Saggu M, Yoo J, et al. Brentuximab a novel antibody
therapy: real‐world use confirms efficacy and tolerability for CD30‐
positive cutaneous lymphoma. Br J Dermatol. 2020;182(3):799‐800.
4. Kempf W, Kerl K, Mitteldorf C. Cutaneous CD30‐positive T‐cell
lymphoproliferative disorders‐clinical and histopathologic features,
differential diagnosis, and treatment. Semin Cutan Med Surg.
2018;37(1):24‐29.
5. Mitteldorf C, Stadler R, Sander CA, Kempf W. Folliculotropic
mycosis fungoides. J Dtsch Dermatol Ges. 2018;16(5):543‐557.
6. Mourad A, Gniadecki R. Overall survival in mycosis fungoides: a
systematic review and meta‐analysis. J Invest Dermatol.
2020;140(2):495‐497.
7. Trautinger F, Eder J, Assaf C, et al. European Organisation for
Research and Treatment of Cancer consensus recommendations for
the treatment of mycosis fungoides/Sezary syndrome ‐update 2017.
Eur J Cancer. 2017;77:57‐74.
8. Willemze R, Hodak E, Zinzani PL, Specht L, Ladetto M, Committee
EG. Primary cutaneous lymphomas: ESMO Clinical Practice Guide-
lines for diagnosis, treatment and follow‐up. Ann Oncol.
2018;29(Suppl 4):iv30‐iv40.
9. Iqbal M, Reljic T, Ayala E, et al. Efficacy of allogeneic hematopoietic
cell transplantation in cutaneous T cell lymphoma: results of a sys-
tematic review and meta‐analysis. Biol Blood Marrow Transpl.
2020;26(1):76‐82.
10. Lindahl LM, Willerslev‐Olsen A, Gjerdrum LMR, et al. Antibiotics
inhibit tumor and disease activity in cutaneous T‐cell lymphoma.
Blood. 2019;134(13):1072‐1083.
11. Klemke CD, Booken N, Weiss C, et al. Histopathological and
immunophenotypical criteria for the diagnosis of Sezary syndrome in
differentiation from other erythrodermic skin diseases: a European
Organisation for Research and Treatment of Cancer (EORTC)
Cutaneous Lymphoma Task Force Study of 97 cases. Br J Dermatol.
2015;173(1):93‐105.
12. Prieto‐Torres L, Rodriguez‐Pinilla SM, Onaindia A, Ara M, Requena
L, Piris MA. CD30‐positive primary cutaneous lymphoproliferative
disorders: molecular alterations and targeted therapies. Haemato-
logica. 2019;104(2):226‐235.
13. Kempf W, Pfaltz K, Vermeer MH, et al. EORTC, ISCL, and USCLC
consensus recommendations for the treatment of primary cuta-
neous CD30‐positive lymphoproliferative disorders: lymphomatoid
papulosis and primary cutaneous anaplastic large‐cell lymphoma.
Blood. 2011;118(15):4024‐4035.
14. Gayden T, Sepulveda FE, Khuong‐Quang DA, et al. Germline
HAVCR2 mutations altering TIM‐3 characterize subcutaneous pan-
niculitis‐like T cell lymphomas with hemophagocytic lymphohistio-
cytic syndrome. Nat Genet. 2018;50(12):1650‐1657.
15. Petrella T, Maubec E, Cornillet‐Lefebvre P, et al. Indolent CD8‐
positive lymphoid proliferation of the ear: a distinct primary cuta-
neous T‐cell lymphoma? Am J Surg Pathol. 2007;31(12):1887‐1892.
How to cite this article: Kempf W, Mitteldorf C. Cutaneous T‐
cell lymphomas—An update 2021. Hematological Oncology.
2021;39(S1):46–51. https://doi.org/10.1002/hon.2850
KEMPF AND MITTELDORF
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51
Received: 18 February 2021
DOI: 10.1002/hon.2846
SUPPLEMENT ARTICLE
What's new in peripheral T‐cell lymphomas
Stefano Luminari
1,2
|Tetiana Skrypets
1,3
1
Surgical, Medical and Dental Morphological
Sciences Related to Transplant, Oncology and
Regenerative Medicine, University of Modena
and Reggio Emilia, Reggio Emilia, Italy
2
Hematology Unit, Azienda USL IRCCS of
Reggio Emilia, Reggio Emilia, Italy
3
PhD Programm in Clinical and Experimental
Medicine, University of Modena and Reggio
Emilia, Italy
Correspondence
Stefano Luminari, Medical and Dental
Department of Morphological Sciences
Related to Transplant, Oncology and
Regenerative Medicine, University of Modena,
Viale risorgimento 80, 42123 Reggio Emilia,
Italy.
Email: sluminari@unimore.it
Abstract
Peripheral T‐cell lymphomas (PTCLs) are a rare, heterogeneous group of hemato-
logical malignancies with extremely poor prognosis for almost all subtypes. The
diverse clinicopathological features of PTCLs make accurate diagnosis, prognosis,
and choice of optimal treatment strategies difficult. Moreover, the best therapeutic
algorithms are still under debate due to the extrapolated approaches developed for
B‐cell lymphomas and to the absence of few treatment protocol specifically
developed for PTCLs. Some advances have been made with CD30 monoclonal
antibody, mainly for anaplastic large‐cell lymphomas, with improvements in
progression‐free survival and overall survival. Several new drugs are under evalu-
ation in clinical trials, although not all the results are as encouraging as expected. In
this review, we briefly present the most updated information on diagnosis, prog-
nostication, and treatment strategies in PTCLs.
KEYWORDS
chemotherapy, novel agents, peripheral T‐cell lymphoma, prognostic factors
1
|
INTRODUCTION
Peripheral T‐cell lymphomas (PTCLs) comprise a heterogeneous
subgroup of rare hematological malignancies originating from post-
thymic lymphocytes. From different available data, PTCLs account
for approximately 5%–15% of all lymphomas in Western countries,
with an incidence of 0.5–2 per 100,000 people per year.
1,2
Four main
clinical subtypes have been identified: nodal, leukemic, disseminated,
and cutaneous PTCLs. From a pathologic point of view, the most
recent edition of the World Health Organization (WHO) Classifica-
tion of lymphomas identifies around 30 subtypes of PTCLs, now also
defined as mature T‐cell lymphomas (MTCLs), some of which are
extremely rare. The most common MTCL subtypes are PTCL not
otherwise specified (NOS), angioimmunoblastic T‐cell lymphoma
(AITL), anaplastic large‐cell lymphoma (ALCL), and natural killer (NK)/
T‐cell lymphoma (NKTCL).
1,3,4
With the exception of cutaneous T‐cell
lymphomas (CTCL), which are usually characterized by an indolent
course, and of anaplastic lymphoma kinase (ALK) positive ALCL, all
other MTCLs are associated with an aggressive course and poor
outcomes, with 5‐year survival rates across subtypes of 30%.
3
Improvement in the approach to MTCL is proceeding slowly, with
advances in recent years seen in improving the classification of
MTCL, patient management and prognostication, and treatment.
In the 2016 revision of the WHO of mature T‐cell neoplasms,
nodal lymphomas of T follicular helper (TFH) cell origin were
introduced. AITL is the most studied TFH subtype, but an addi-
tional 40% of cases of PTCL‐NOS have been shown to share some
of the clinical and pathological features of the TFH phenotype,
which requires the expression of at least two of three TFH‐related
antigens, including PD1, CD10, BCL6, CXCL13, ICOS, SAP, and
CCR5. Recurrent genetic abnormalities associated with TFH
phenotype include mutations of in epigenetic modifiers (TET2,
IDH2, DNMT3A), RHOA, and T‐cell receptor associated genes
(PLCG1, CD28, VAV1, FYN).
3,5
Among the non‐TFH PTCL‐NOS,
gene expression profiling and microRNA profiling studies have
delineated two additional subgroups: those with an increased
This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, pro-
vided the original work is properly cited.
© 2021 The Authors. Hematological Oncology published by John Wiley & Sons Ltd.
52
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Hematological Oncology. 2021;39(S1):52–60. wileyonlinelibrary.com/journal/hon
expression of GATA3 and those with an increased expression of
TBX21.
3,5
The GATA3 group is associated with poor outcomes and
has more loss or mutation of tumor suppressor genes including
TP53, PTEN, PRDM1, and CDKN2A/B, and gains in STAT3, REL,
and MYC oncogenes.
6
The TBX21 group is enriched with alter-
ations of genes involved in DNA methylation.
7
These three groups
are added to other previously characterized subtypes with specific
cell of origin, which include ALCL, adult T‐cell leukemia/lymphoma,
and gamma‐delta PTCL. The better characterization of the cell of
origin in PTCL is advantageous in the classification of these lym-
phomas as it reduces the undefined basket of PTCL‐NOS and
provides a strong rationale for determining the most effective
therapies in these lymphomas. Immunomodulatory agents and
epigenetic modifiers are more suitable for TFH subtypes, while
phosphatidylinositol 3‐kinase (PI3K) inhibitors, hypomethylating
agents, and Janus kinase/signal transducer and activator of tran-
scription (JAK/STAT) inhibitors might find a better role in GATA3
or TBX21 subtypes.
8
1.1
|
Prognosis and staging
In the last two decades, many studies have been conducted to
identify and validate clinical and biological factors that can be used
to predict the heterogenous outcome of PTCL patients. Several of
these studies have confirmed that a poor Eastern Cooperative
Oncology Group Scale of Performance Status score, extranodal
involvement, advanced disease, bulky, Ki67, and a high lactate de-
hydrogenase rate correlate with shorter overall survival (OS).
9–11
The International Prognostic Index (IPI) was formally validated in
PTCL
1,12
but the lack of clearly defined risk groups prompted the
search for PTCL‐specific prognostic indexes.
9,11
The Fondazione
Italiana Linfomi defined the first Prognostic Index for PTCL‐NOS
(PIT), which stratifies patients into four distinct groups; the PIT
showed an independent correlation with OS. Subsequently, PIT
was updated to modified PIT by replacing bone marrow involve-
ment with Ki67 rate expression.
10
A new model, the T‐cell
score, has recently been defined by using the prospectively
collected data registered in the T‐cell Project.
13
More recently,
novel prognostic indexes have been identified and validated for
specific PTCL subtypes, including enteropathy‐associated T‐cell
lymphoma (EATCL) and nasal‐type extranodal NKTCL. As shown
in Table 1, all available prognostic indexes share the same structure
of categorical scores based on simple laboratory and clinical fea-
tures. Although all of these indexes have been formally validated,
the accuracy of prognostication in PTCL remains suboptimal; thus,
more prognostic studies that take into account novel biomarkers
and novel prognostic features are warranted. Among recent ad-
vances, a better definition of response by means of
18
F‐
fluorodeoxyglucose positron emission tomography (FDG‐PET) may
play an important role in PTCL management and decision making.
14
PTCLs are listed among FDG‐avid diseases, and several studies
have already confirmed the role of metabolic tumor volume and of
interim and end‐of‐treatment FDG‐PET to predict outcomes.
15,16
Although promising, data regarding the role of metabolic response
in PTCLs are very preliminary and thus need to be confirmed by
larger studies.
1.2
|
Treatment
The optimal management of patients with PTCL, which is disputed, is
in any case limited to few options, all with unsatisfactory efficacy.
None of the currently available recommendations are based on high‐
quality evidence, and few well‐designed randomized clinical trials
(RCTs) have been conducted to support therapeutic choices. The
currently recommended treatment strategy for PTCLs derives mostly
from B‐cell lymphoma treatment strategies, with the recommended
use of an aggressive approach with anthracycline‐based poly-
chemotherapy (i.e., CHOP or CHOEP) and with autologous stem cell
transplant (autoSCT) to consolidate response to first‐line therapy or
to manage relapsed patients.
17
Regarding the role of anthracyclines in PTCL, while their role is
still debated, anthracycline void regimens have so far failed
to demonstrate their superiority to CHOP.
17
Based on a recent
meta‐analysis, the 5‐year OS achieved with this approach was
36.6%.
18
Several attempts have been made to improve the poor results
achieved with CHOP. These include the addition of novel agents
and the intensification of therapy. Some clinical studies on etopo-
side intensification of standard CHOP have shown conflicting re-
sults. However, the addition of etoposide has shown better
progression‐free survival (PFS), especially in patients with ALCL,
in those with favorable risk factors, and in patients age ≤60
years.
12,19–21
The results of three randomized trials that evaluated the efficacy
of adding a novel agent to the CHOP backbone are available.
One prospective trial combined alemtuzumab, an anti‐CD52
monoclonal antibody, with CHOP; it failed to show improved out-
comes compared to chemotherapy alone.
22
Another randomized trial
compared standard CHOP with CHP (cyclophosphamide, vincristine,
prednisone) combined with the anti‐CD30 antibody‐drug conjugate
brentuximab vedotin (BV‐CHP; ECHELON‐2 trial).
23
This trial, which
enrolled 452 treatment naïve CD30‐positive PTCLs, demonstrated
improved PFS and OS rates for the BV‐CHP combination.
23
Most of
the patients included in this trial (about 75%) had ALCL, with clearly
positive results for this subtype. However, the scientific community
was left without any clear demonstration of the efficacy of BV‐CHP
in non‐ALCL CD30‐positive subtypes.
A third trial compared CHOP with CHOP +the histone deace-
tylase inhibitor romidepsin, showing promising single‐agent activity
in relapsed refractory patients (ROCHOP trial).
24
The ROCHOP RCT
conducted by the LYSA group enrolled 421 patients with PTCL who
were not planned to receive autoSCT or allogeneic SCT (alloSCT).
The median PFS (mPFS) for patients in the experimental arm was 12
months (9–25.8), without significant difference compared to the
LUMINARI AND SKRYPETS
-
53
reference arm (mPFS 10.2 months [7.4–13.2]; hazard ratio: 0.81; 95%
confidence interval: 0.63–1.04). Although this study was not able to
confirm the initial hypothesis of the superiority of Ro‐CHOP, the
subgroup analysis seems to suggest that the novel combination acts
differently in different PTCL subtypes, with relatively higher activity
observed for AITLs.
24
In summary, even if associated with unsatisfactory results, CHOP
chemotherapy should still be considered as the reference therapy for
most PTCL subtypes with the main exception of ALCL for which BV‐
CHP is the preferred recommended option and of NKTCL. The use of
CHOEP is supported by low quality of evidence but can be consid-
ered as a reasonable option in young and fit subjects with non‐ALCL
PTCLs.
The use of high‐dose chemotherapy followed by autoSCT in
first complete remission (CR1) is recommended by most of the
available guidelines
17,25
(Table 2). Several groups have reported
that achieving CR before autoSCT is a significant independent
predictor of improved survival in patients with PTCL receiving
upfront autoSCT.
26–28
However, there have been no RCTs specif-
ically designed to evaluate upfront autoSCT in comparison
with observation in CR1 for PTCL.
29–31
Several retrospective
studies and prospective single‐arm phase II trials have reported
encouraging results with this approach (Table 3). The largest
prospective phase II study, published by the Nordic Group (NLG‐T‐
01), included 160 patients with PTCLs; 72% of patients underwent
autoSCT in first remission after six courses of CHOEP chemo-
therapy.
32
All nodal PTCL subtypes were included, with the
exception of A.
1.2.1
|
ALK‐positive ALCLs
One hundred thirty patients achieved CR (63%) or partial response
(PR; 37%), and 115 (88.5%) underwent ASCT. Overall, the 5‐year
OS and PFS for the intention‐to‐treat population were 51% and
44%, respectively. Considering subtype distribution, better out-
comes were observed for ALK‐negative ALCL than for other sub-
types.
32
In a second study by Reimer et al.,
33
83 patients with
PTCL were enrolled, with the exclusion of CTCL and of ALK‐
positive ALCL. Fifty‐nine patients (71%) completed stem cell
mobilization after CR (66%) or PR (34%) and 55 underwent
autoSCT. The 3‐year OS was 48%.
TABLE 1Prognostic models in PTCL
Variable
IPI PIT IPTCLP mPIT TCS AITL PINK EPI
International
NHL Prognostic
Factors Project (1993)
Gallamini
et al.
(2004)
Vose
et al.
(2008)
Went
et al.
(2006)
Federico
et al.
(2018)
Hong
et al.
(2018)
Kim
et al.
(2016)
de Baaij
et al.
(2015)
Age >60 X X X X X X
ECOG ≥1X X X X x X
LDH (abn. values) X X X X X
Stage III–IV X x X X X
ENS >2X X X
BM+X
Plt <150 K/mmc X X
S‐Alb x
Neutrophils x
Ki67 ≥80% X
Anemia (M <13,
F<11g/dl)
X
Serum IgA
(>400 mg/dl)
X
B symptoms X X
Regional
lymph nodes
X
PTCL subset All PTCL‐NOS PTCL‐NOS PTCL‐NOS PTCL‐NOS AITL NK‐TCL EATL
Abbreviations: AITL, angioimmunoblastic T‐cell lymphoma; BM, bone marrow; EATL, entheropathy‐associated T‐cell lymphoma; ENS, extranodal sites;
EPI, EATL prognostic index; IPI, International Prognostic Index; ECOG, Eastern Cooperative Oncology Group; IPTCLP, International Peripheral T‐cell
Lymphoma Project; LDH, lactate dehydrogenase; mPIT, modified Prognostic Index for T‐cell lymphoma; NKTCL, natural killer/T‐cell lymphoma; PINK,
Prognostic Index of natural killer lymphoma; PLT, platelet count, PTCL‐NOS, peripheral T‐cell lymphoma not otherwise specified; S‐Alb, serum albumin;
TCS, T‐cell score.
54
-
LUMINARI AND SKRYPETS
Some recently published studies provide additional insights
into the role of autoSCT in CR1. A real‐world data analysis from
the Swedish Lymphoma Registry found prolonged OS and PFS for
transplanted patients with PTCL‐NOS, AITL, ALK‐negative ALCL
and EATCL after adjustment for confounding factors.
34
However,
the selection of non‐ASCT patients used as the control group may
have been biased by early progressing patients after induction
therapy. Another study was a large multicenter analysis conducted
by the LYSA group. Among the 527 studied cases, a final cohort of
269 patients age less than 65 years with a CR or PR after in-
duction chemotherapy was identified: 78 cases of PTCL‐NOS, 123
cases of AITL, and 68 cases of ALK‐negative ALCL. Overall, 81%
were in CR and 19% in PR; 50% of the final cohort was allocated
to autoSCT (134 patients). Neither the Cox multivariate model nor
the propensity score analysis found any survival advantage in favor
of autoSCT as a consolidation procedure for patients in response
after induction therapy. Subgroup analyses did not reveal any
further difference in terms of response status, disease stage, or
risk category.
35
Recently, Park et al.
36
published their first report
of the large prospective observational COMPLETE study, con-
ducted by 56 U.S. academic centers. This paper described the
outcomes of 119 patients who achieved CR after induction ther-
apy, including 54 PTCL‐NOS, 35 AITL, and 30 ALK‐negative ALCL.
Thirty‐six patients underwent autoSCT; patients with AITL had
significantly improved OS and PFS but patients with other PTCL
subtypes did not. Finally, an exploratory of the ECHELON‐2 trial
was conducted, for the 82 patients with a declared intention to
transplant out of the 177 patients randomized to BV‐CHP arm
(ALK‐positive ALCL were excluded). SCT was in fact performed in
38 patients (27 ALK‐negative ALCL and 11 non‐ALCL patients),
most of whom were from non‐Asian centers, suggesting regional
practice differences. Despite the fact that the ECHELON‐2 study
was not designed to evaluate the role of upfront consolidation
with ASCT, numerical PFS estimates favored the use of con-
solidative SCT in patients with ALK‐negative ALCL and with non‐
ALCL who achieved a CR at the end of induction after frontline
BV‐CHP.
23
Interpreting the results from these studies on the role of
autoSCT consolidation is complicated by the diverse eligibility
criteria adopted, the suboptimal rates of transplantation among PTCL
subtypes, and the differing rates of CR before autoSCT. The decision
to proceed to autoSCT in a subject with PTCL who responds to first‐
line chemotherapy is difficult and should always be discussed with
the individual patient. Researchers are strongly encouraged to run
well‐designed clinical trials that adopt the same up‐to‐date criteria
for response definition (i.e., FDG‐PET). These trials, which would
necessarily require considerable international cooperation, would
hopefully provide data by PTCL subtype.
alloSCT could be identified as alternative option to autoSCT as
consolidation of CR1 patients. Schmitz et al.
37
recently published
data from the first randomized phase 3 trial of auto versus alloSCT as
part of first‐line therapy in poor‐risk PTCLs excluding ALK‐positive
TABLE 2ESMO and NCCN clinical practice guidelines for auto‐alloSCT in PTCLs
PTCLs subtype
Primary diagnosed PTCLs Relapsed/refractory PTCLs
ESMO NCCN ESMO NCCN
PTCL‐NOS PR, CR, transplant
eligible—autoSCT
Clinical trials, or ASCT, or
observation if CR, or
if PR—see rel/ref settings
PR, CR, transplant
eligible—alloSCT (or ASCT)
PR, CR, transplant
eligible—alloSCT (or ASCT)
AITL PR, CR, transplant
eligible—autoSCT
Clinical trials or ASCT or
observation if CR, or if
PR—see rel/ref settings
PR, CR, transplant
eligible—alloSCT (or ASCT)
PR, CR, transplant
eligible—alloSCT (or ASCT)
ALK‐negative
ALCL
PR, CR, transplant
eligible—autoSCT
Clinical trials, or ASCT or
observation if CR, or
if PR—see rel/ref settings
PR, CR, transplant
eligible—alloSCT (or ASCT)
PR, CR, transplant
eligible—alloSCT (or ASCT)
ALK‐positive
ALCL
No further treatment,
Or autoSCT
if high‐risk profile
Only chemotherapy ±ISRT PR, CR, transplant
eligible—alloSCT (or ASCT)
PR, CR, transplant
eligible—alloSCT (or ASCT)
EATL autoSCT Clinical trials, or ASCT, or
observation if CR, or if
PR—see rel/ref settings
PR, CR, transplant
eligible—alloSCT (or ASCT)
PR, CR, transplant
eligible—alloSCT (or ASCT)
HSTCL ASCT or allo if
donor available
CR or PR—preferred alloSCT PR, CR, transplant
eligible—alloSCT (or ASCT)
Preferred alloSCT if eligible
ENKTCL ASCT Stage IV if CR—allo or ASCT PR, CR, transplant eligible—
alloSCT (or ASCT)
AlloSCT (or ASCT)
Abbreviations: AITL angioimmunoblastic T‐cell lymphoma; ALCL, anaplastic large cell lymphoma; alloSCT, allogeneic stem cell transplant; ASCT,
autologous stem cell transplant; CR, Complete remission; EATL, entheropathy‐associated T‐cell lymphoma; ENKTCL, entranodal T‐cell lymphoma;
HSTCL, hepatosplenic T‐cell lymphoma; ISRT, involved site radiotherapy; PR, partial remission; PTCL, peripheral T‐cell lymphoma.
LUMINARI AND SKRYPETS
-
55
ALCLs. The trial enrolled 18–60‐year‐old patients of all stages and
IPI and was planned to detect an improvement of event‐free survival
at 3 years from 35% achieved with autoSCT to 60% by alloSCT in the
intent‐to‐treat population. After the enrollment of 104 patient
randomization and recruitment was prematurely stopped because a
planned interim analysis had shown that it was highly unlikely to
meet the primary endpoint. The transplant‐related mortality
observed contributed to this result. In conclusion, alloSCT cannot be
recommended as consolidation therapy for CR1 PTCL patients due to
the lack of evidence and because of it toxicity profile. The only
TABLE 3Available prospective and retrospective studies of ASCT in PTCLs
Study NPTCLs subtype Time of transplant Response (%) PFS (years) OS (years)
Reimer et al. (2004) 83 39% PTCL‐NOS Upfront CR: 47 36% (4) 48% (4)
Prospective 16% ALCL (ALK‐negative) PR: 24
33% AITL
Corradini et al. (2006) 62 45% PTCL‐NOS Upfront CR: 56 EFS reported:
30% (12)
34% (2)
Prospective 30% ALCL (ALK‐positive) PR: 16
16% AITL
Rodriguez et al. (2007)
Prospective
26 42% PTCL‐NOS Upfront CR: 65 53% (3) 86% (3)
31% ALCL (ALK‐positive) PR: 8
27% AITL
Mercadal et al. (2008) 41 49% PTCL‐NOS Upfront CR: 49 30% (4) 39% (4)
Prospective 29% AITL PR: 10
5% HSTCL
5% T/NK
d'Amore et al. (2012) 160 39% PTCL‐NOS Upfront CR: 83 44% (5) 51% (5)
Prospective 19% ALCL (ALK‐negative) PR: 31
19% AITL
13% EATL
4% panniculitis‐like
3% T/NK
Fossard et al. (2018) 134 34% PTCL‐NOS Upfront CR: 75 46.3% (5) 59.2% (5)
Retrospective 23% ALCL (ALK‐negative) PR: 25
43% AITL
Roerden et al. (2019) 58 25.9% AITL Upfront (40 pts) CR: 75 Upfront ASCT Upfront ASCT
22.4% EATCL Relapse/refractory
(18 pts)
PR: 25 44% (5) 53% (5)
20.7% PTCL‐NOS ASCT in first
relapse
ASCT in first
relapse
Retrospective 19% ALCL (ALK‐negative) 60.6% (5) 77.4% (5)
8.6% ALCL (ALK‐positive)
3.4% T/NK
Park et al. (2019) 36 42% PTCL‐NOS Upfront CR: 63 44% (5) 51% (5)
Prospective 11% ALCL (ALK‐negative) PR: 37
47% AITL
Abbreviations: AITL, angioimmunoblastic T‐cell lymphoma; ALCL, anaplastic large cell lymphoma; ALK, anaplastic lymphoma kinase negative; ASCT,
auto stem cell transplant; CR complete response; EATCL, enteropathy‐associated T‐cell lymphoma; EATL, entheropathy‐associated T‐cell lymphoma;
EFS, event‐free survival; HSTCL, hepatosplenic T‐cell lymphomas; OS overall survival; PFS, progression‐free survival; PR, partial response; PTCLs,
peripheral T‐cell lymphomas; PTCL‐NOS, peripheral T‐cell lymphomas not otherwise specified; T/NK, T‐cell lymphoma/natural killer.
56
-
LUMINARI AND SKRYPETS
exception to this general statement might be represented by hep-
atosplenic T‐cell lymphomas for whom a systematic review of 44
cases treated with alloSCT at first or second relapse demonstrated a
3‐year relapse‐free survival of 42% and OS of 56%.
38
1.3
|
Relapsed/refractory disease
Approximately 70% of patients with PTCL are expected to develop
relapsed or refractory disease after first‐line therapy.
39,40
A dismal
outcome can be expected for these patients, with median OS of a few
months, even for those who are able to proceed to salvage therapy.
39
Among the options available, the effectiveness of autoSCT in
relapsed disease is uncertain due to the frequent use of autoSCT in
CR1 in eligible patients, and because the salvage therapies available
for relapsed PTCLs have very limited activity, thereby further
reducing the feasibility of an autoSCT program when planned.
Available salvage regimens were previously developed as a first‐line
strategies mostly for B‐cell malignancies, from them well‐known ICE
(ifosfamide, carboplatin, etoposide), DHAP (high‐dose cytarabine,
cisplatin, dexamethasone), GDP (gemcitabine, cisplatin, dexametha-
sone), and ESHAP (etoposide, cytarabine, cisplatin, and methylpred-
nisolone). Despite the fact that these regimens were previously
studied for aggressive lymphomas, due to the rarity of PTCLs a small
number of patients were included without independent subset
analysis.
41–44
Even if limited by a low power due, a subset analysis of
the Canadian Cancer Trials Group LY.12 randomized phase 3 study
was not able to confirm DHAP superiority over GDP in PTCLs.
45
In
relapsed/refractory PTCLs, alloSCT is also a feasible option in almost
all subtypes after failing prior autoSCT.
17,25,46
However, nonrelapse
mortality varies from 8.2% to 40%.
47–49
These scatter data suggest
that it is necessary to carefully select possible candidates for alloSCT.
Several new agents have been tested in the relapsed refractory
setting, and, while some have already received formal approval for
clinical use, approval is not uniform across countries. These include
the anti‐CD30 antibody‐drug conjugate BV, pralatrexate (approved
in the United States only), and four histone deacetylase inhibitors
(HDAC): romidepsin (United States only), belinostat (United States
only), vorinostat (United States only), and chidamide (China only).
Results achieved with these agents are very similar with CR rates of
10%–25% and with a median PFS of less than 1 year.
1.4
|
Novel agents
Pharmacology research is very active in PTCL, and therapeutic
development is mainly driven by advances in the understanding of
the biology of the disease (Table 4).
TABLE 4Activity of novel agents from clinical trials in relapsed refractory PTCLs
Drug PTCL subtype No. of patients Study phase ORR; CR Reference
Pralatrexate PTCL 111 2 29%; 11% O'Connor et al. (2011)
Romidepsin PTCL 131 2 25%; 15% Coiffier et al. (2012)
Brentuximab vedotin CD30 +PTCL 34 2 41%; 24% Horwitz et al. (2012); Pro et al. (2012)
ALCL 58 86%; 57%
Belinostat PTCL 129 2 25.8%; 10.8% O'Connor et al. (2015)
Bendamustine PTCL 60 2 50%; 28% Damal et al. (2013)
Mogamulizumab CCR4 +PTCL/CTCL 29 1 34%; 17% Ogura et al. (2014)
Lenalidomide PTCL 39 2 26%; 8% Tournishey et al. (2015)
Copanlisib NHL 17 2 21%; 14% Dreyling et al. (2017)
Cerdulatinib PTCL 18 2a 43% Horwitz et al. (2018)
Duvelisib PTCL +CTCL 16 1 50%; 19% Horwitz et al. (2018)
Alisertib PTCL 271 3 33%; 18% O'Connor et al. (2019)
Tipifarnib AITL, CXCL12 +TCL 43 Interim analysis 45% Witzig et al. (2019)
Pembrolizumab PTCL 18 33%; 27% Barta et al. (2019)
Panobinostat +bortezomib PTCL 25 1 43%; 22% Tan et al. (2015)
Gemcitabine +romidepin PTCL 20 1 30%; 15% Pellegrini et al. (2016)
Pralatrexate +romidepsin TCL 14 1 71%; 29% Amengual et al. (2018)
5‐Azacytidine +romidepsin PTCL 31 1 73%; 55% O'Connor et al. (2019)
Abbreviations: AITL, angioimmunoblastic T‐cell lymphoma; ALCL, anaplastic large‐cell lymphoma; CCR4, chemokine receptor‐4; CR, complete response;
CTCL, cutaneous T‐cell lymphoma; CXCL12, C‐X‐C motif chemokine 12; NHL, non‐Hodgkin lymphoma; ORR, overall response rate; PTCL, peripheral T‐
cell lymphoma; TCL, T‐cell lymphoma.
LUMINARI AND SKRYPETS
-
57
The frequent alteration of the epigenetic machinery in PTCL,
mainly of the TFH phenotype, justifies strong rationale for the search
of novel HDAC inhibitors and to test the efficacy of combining more
than one epigenetic modifier. A recent phase 1 combination trial of 5‐
azacitidine and romidepsin reported very interesting OR and CR
rates of 73% and 55%, respectively.
50
Inhibition of spleen tyrosine kinase (SYK) signaling and of PI3K
pathways have also been investigated, with promising results from
phase I and II studies. Cerdulatinib is an oral SYK, JAK1, JAK3, and
Tyk2 inhibitor; in a phase IIa study on 41 PTCL patients, it was able
to produce an overall response rate of 34%, with 27% CR rates.
51
Among PI3K inhibitors, the oral duvelisib was used in a phase I study
with 16 PTCL and 19 CTCL patients. The overall response rate was
50% for the PTCL patients and the median PFS was 8.4 months.
45
The same agent has been evaluated in combination with romidepsin,
showing greater activity in AITL and PTCL‐NOS (overall
response rates 74% and 64%, respectively, CR rates 63% and 36%,
respectively).
52
A promising therapeutic strategy in PTCL is represented by
targeting of tumor microenvironment. Blocking the PD1 interaction
with its ligand is justified by the finding of an increased expression of
PD‐L1 in both malignant and stromal cells of several PTCL subtypes.
Indeed, some activity of anti‐PD1 agents in PTCL has been described
by phase I studies,
53
and more convincing results have been achieved
with NKTCL. The use of PD1 blockers, however, has also been
associated with cases of hyperprogression, thus making further
clarification of PD1 inhibition in PTCL urgently needed.
Finally, cellular therapy based on the concept of chimeric antigen
receptor T cells is also being developed for T‐cell lymphomas,
54
as is
the use of bispecific antibodies targeting both CD30 and CD16A.
55
2
|
CONCLUSIONS
Management of PTCL patients continues to be a real challenge for
hematologist–oncologists. The oversimplified approach that has been
used for many years, replicating the rules of B‐cell lymphoma man-
agement, is clearly unsatisfactory and requires radical reassessment.
New insights into the biology of the disease and a renewed interest
on the part of the scientific community in the management of PTCL
have led to the identification of new targets and to confirming the
activity of new agents, which are now moving PTCLs into the era of
targeted therapy. Moreover, taking into account the different biology
and unique behavior of PTCL subtypes, each with a different
response to therapy, has become indispensable; these differences
result in more difficulties in interpreting the available data and in
designing future trials. PTCL remains a challenging disease which
requires massive international cooperation.
ACKNOWLEDGMENTS
The authors are grateful to MS Jacqueline Costa for her support in
reviewing the manuscript
CONFLICT OF INTERESTS
Luminari served as advisor for Roche, BMS, Jannsen, Regeneron,
Genmab, Gilead. Skrypets has no conflict of interest to declare.
ORCID
Stefano Luminari https://orcid.org/0000-0001-8446-2285
Tetiana Skrypets https://orcid.org/0000-0002-2276-869X
REFERENCES
1. Vose J, Armitage J, Weisenburger D, International T‐Cell Lymphoma
Project. International peripheral T‐cell and natural killer/T‐cell
lymphoma study: pathology findings and clinical outcomes. J Clin
Oncol. 2008;26(25):4124‐4130.
2. Bellei M, Chiattone CS, Luminari S, et al. T‐cell lymphomas in South
America and Europe. Rev Bras Hematol Hemoter. 2011;34(1):42‐47.
https://doi.org/10.5581/1516‐8484.20120013
3. Swerdlow SH, Campo E, Pileri SA, et al. The 2016 revision of the
World Health Organization classification of lymphoid neoplasms.
Blood. 2016;127(20):2375‐2390.
4. Bellei M, Foss FM, Shustov AR, et al. The outcome of peripheral
T‐cell lymphoma patients failing first line therapy: a report from the
prospective, International T‐Cell Project. Haematologica. 2018;
103(7):1191‐1197.
5. Swerdlow SH, Campo E, Harris NL, et al. WHO Classification of Tu-
mours of Haematopoietic and Lymphoid Tissues. Lyon, France: Inter-
national Agency for Research on Cancer; 2017.
6. Heavican TB, Bouska A, Yu J, et al. Genetic drivers of oncogenic
pathways in molecular subgroups of peripheral T‐cell lymphoma.
Blood. 2019;133(15):1664‐1676. https://doi.org/10.1182/blood‐
2018‐09‐872549
7. Wang T, Feldman AL, Wada DA, et al. GATA‐3 expression identifies
a high‐risk subset of PTCL, NOS with distinct molecular and clinical
features. Blood. 2014;123(19):3007‐3015. https://doi.org/10.1182/
blood‐2013‐12‐544809
8. Pinter‐Brown LC. Strategies for aggressive T‐cell lymphoma: divide
and conquer. Hematology Am Soc Hematol Educ Program.
2020;2020(1):154‐159. https://doi.org/10.1182/hematology.20200
00101
9. Weisenburger DD, Savage KJ, Harris NL, et al. Peripheral T‐cell
lymphoma, not otherwise specified: a report of 340 cases from the
International Peripheral T‐cell Lymphoma Project. Blood. 2011;117:
3402‐3408.
10. Went P, Agostinelli C, Gallamini A, et al. Marker expression in pe-
ripheral T‐cell lymphoma: a proposed clinical‐pathologic prognostic
score. J Clin Oncol. 2006;24:2472‐2479.
11. Gallamini A, Stelitano C, Calvi R, et al. Peripheral T‐cell lymphoma
unspecified (PTCL‐U): a new prognostic model from a retrospective
multicentric clinical study. Blood. 2004;103:2474‐2479.
12. Schmitz N, Trümper L, Ziepert M, et al. Treatment and prognosis of
mature T‐cell and NK‐cell lymphoma: an analysis of patients with
T‐cell lymphoma treated in studies of the German High‐Grade Non‐
Hodgkin Lymphoma Study Group. Blood. 2010;116:3418‐3425.
13. Federico M, Bellei M, Marcheselli L, et al. Peripheral T cell lym-
phoma, not otherwise specified (PTCL‐NOS). A new prognostic
model developed by the International T Cell Project Network. Br J
Haematol. 2018;181(6):760‐769. https://doi.org/10.1111/bjh.15258
14. Cheson BD. PET/CT in lymphoma: current overview and future di-
rections. Semin Nucl Med. 2018;48(1):76‐81. https://doi.org/10.
1053/j.semnuclmed.2017.09.007
15. Pellegrini C, Argnani L, Broccoli A, et al. Prognostic value of interim
positron emission tomography in patients with peripheral T‐cell
lymphoma. Oncologist. 2014;19:746‐750.
58
-
LUMINARI AND SKRYPETS
16. El‐Galaly TC, Pedersen MB, Hutchings M, et al. Utility of interim and
end‐of‐treatment PET/CT in peripheral T‐cell lymphomas: a review
of 124 patients. Am J Hematol. 2015;90:975‐980.
17. d'Amore F, Gaulard P, Trumper L, et al. Peripheral T‐cell lymphomas:
ESMO Clinical Practice Guidelines for diagnosis, treatment and
follow‐up. Ann Oncol. 2015;26(suppl 5):v108‐v115.
18. AbouYabis AN, Shenoy PJ, Sinha R, Flowers CR, Lechowicz MJ. A
systematic review and meta‐analysis of front‐line anthracycline‐
based chemotherapy regimens for peripheral T‐cell lymphoma.
ISRN Hematol. 2011;2011:623924. https://doi.org/10.5402/2011/
623924
19. Lage LAPC, Cabral TCS, Costa RO, et al. Primary nodal peripheral
T‐cell lymphomas: diagnosis and therapeutic considerations. Rev
Bras Hematol Hemoter. 2015;37:277‐284.
20. Dearden CE, Johnson R, Pettengell R, et al. Guidelines for the
management of mature T‐cell and NK‐cell neoplasms (excluding
cutaneous T‐cell lymphoma). Br J Haematol. 2011;153:451‐485.
21. Karakas T, Bergmann L, Stutte HJ, et al. Peripheral T‐cell lymphomas
respond well to vincristine, adriamycin, cyclophosphamide, predni-
sone and etoposide (VACPE) and have a similar outcome as high‐
grade B‐cell lymphomas. Leuk Lymphoma. 1996;24(1‐2):121‐129.
22. Wulf GG, Altmann B, Altmann B, et al. Alemtuzumab plus CHOP
versus CHOP in elderly patients with peripheral T‐cell lymphoma:
the DSHNHL2006‐1B/ACT‐2 trial. Leukemia. 2021;35(1):143‐155.
https://doi.org/10.1038/s41375‐020‐0838‐5
23. Horwitz S, O'Connor OA, Pro B, et al. Brentuximab vedotin with
chemotherapy for CD30‐positive peripheral T‐cell lymphoma
(ECHELON‐2): a global, double‐blind, randomised, phase 3 trial.
Lancet. 2019;393(10168):229‐240. https://doi.org/10.1016/S0140‐
6736(18)32984‐2
24. Bachy E, Camus V, Thieblemont C, et al. Final analysis of the Ro‐
CHOP Phase III (conducted by LYSA): romidepsin plus CHOP in
patients with peripheral T‐cell lymphoma. 62nd American Society of
Hematology (ASH) Annual Meeting and Exposition; 2020.
25. https://www.nccn.org/professionals/physician_gls/pdf/t‐cell_blocks.
pdf. Accessed 17 Feb 2021
26. Corradini P, Tarella C, Zallio F, et al. Long‐term follow‐up of patients
with peripheral T‐cell lymphomas treated up‐front with high‐dose
chemotherapy followed by autologous stem cell transplantation.
Leukemia. 2006;20:1533‐1538.
27. Kyriakou C, Canals C, Goldstone A, et al. High‐dose therapy and
autologous stem‐cell transplantation in angioimmunoblastic lym-
phoma: complete remission at transplantation is the major deter-
minant of outcome lymphoma working party of the European Group
for Blood and Marrow Transplantation. J Clin Oncol. 2008;26(2):
218‐224.
28. Rodriguez J, Conde E, Gutierrez A, et al. The adjusted International
Prognostic Index and β‐2‐microglobulin predict the outcome after
autologous stem cell transplantation in relapsing/refractory pe-
ripheral T‐cell lymphoma. Haematologica. 2007;92:1067‐1074.
29. Stiff PJ, Unger JM, Cook JR, et al. Autologous transplantation as
consolidation for aggressive non‐Hodgkin's lymphoma. N Engl J Med.
2013;369:1681‐1690.
30. Mounier N, Gisselbrecht C, Brière J, et al. Prognostic factors in pa-
tients with aggressive non‐Hodgkin's lymphoma treated by front‐
line autotransplantation after complete remission: a cohort study
by the Groupe d'Etude des Lymphomes de l'Adulte. J Clin Oncol.
2004;22:2826‐2834.
31. Mounier N, Gisselbrecht C, Brière J, et al. All aggressive lymphoma
subtypes do not share similar outcome after front‐line auto-
transplantation: a matched‐control analysis by the Groupe d'Etude
des Lymphomes de l'Adulte (GELA). Ann Oncol. 2004;15:1790‐1797.
32. d'Amore F, Relander T, Lauritzsen GF, et al. Up‐front autologous
stem‐cell transplantation in peripheral T‐cell lymphoma: NLG‐T‐01.
J Clin Oncol. 2012;30:3093‐3099.
33. Reimer P, Schertlin T, Rüdiger T, et al. Myeloablative radio-
chemotherapy followed by autologous peripheral blood stem cell
transplantation as first‐line therapy in peripheral T‐cell lymphomas:
first results of a prospective multicenter study. Hematol J.
2004;5(4):304‐311. https://doi.org/10.1038/sj.thj.6200359
34. Ellin F, Landström J, Jerkeman M, Relander T. Real‐world data on
prognostic factors and treatment in peripheral T‐cell lymphomas: a
study from the Swedish Lymphoma Registry. Blood. 2014;
124(10):1570‐1577.
35. Fossard G, Broussais F, Coelho I, et al. Role of up‐front autologous
stem‐cell transplantation in peripheral T‐cell lymphoma for patients
in response after induction: an analysis of patients from LYSA cen-
ters. Ann Oncol. 2018;29(3):715‐723. https://doi.org/10.1093/
annonc/mdx787
36. Park SI, Horwitz SM, Foss FM, et al. The role of autologous stem cell
transplantation in patients with nodal peripheral T‐cell lymphomas
in first complete remission: report from COMPLETE, a prospective,
multicenter cohort study. Cancer. 2019;125(9):1507‐1517. https://
doi.org/10.1002/cncr.31861
37. Schmitz N, Truemper LH, Bouabdallah K, et al. A randomized phase 3
trial of auto vs. allo transplantation as part of first‐line therapy in
poor‐risk peripheral T‐NHL. Blood. 2020. https://doi.org/10.1182/
blood.2020008825
38. Rashidi A, Cashen AF. Outcomes of allogeneic stem cell trans-
plantation in hepatosplenic T‐cell lymphoma. Blood Cancer J.
2015;5(6):e318. https://doi.org/10.1038/bcj.2015.43
39. Mak V, Hamm J, Chhanabhai M, et al. Survival of patients with
peripheral T‐cell lymphoma after first relapse or progression:
spectrum of disease and rare long‐term survivors. J Clin
Oncol. 2013;31(16):1970‐1976. https://doi.org/10.1200/JCO.2012.
44.7524
40. Dreyling M, Thieblemont C, Gallamini A, et al. ESMO Consensus
conferences: guidelines on malignant lymphoma. Part 2: marginal
zone lymphoma, mantle cell lymphoma, peripheral T‐cell lymphoma.
Ann Oncol. 2013;24:857‐877.
41. Jerkeman M, Leppä S, Kvaløy S, Holte H. ICE (ifosfamide, carbo-
platin, etoposide) as second‐line chemotherapy in relapsed or pri-
mary progressive aggressive lymphoma—the Nordic Lymphoma
Group experience. Eur J Haematol. 2004;73:179‐182.
42. Philip T, Chauvin F, Armitage J, et al. Parma international protocol:
pilot study of DHAP followed by involved‐field radiotherapy and
BEAC with autologous bone marrow transplantation. Blood.
1991;77:1587‐1592.
43. Zelenetz AD, Hamlin P, Kewalramani T, Yahalom J, Nimer S,
Moskowitz CH Ifosfamide, carboplatin, etoposide (ICE)‐based
second‐line chemotherapy for the management of relapsed and re-
fractory aggressive non‐Hodgkin's lymphoma. Ann Oncol.
2003;14(suppl 1):i5‐i10.
44. Velasquez WS, McLaughlin P, Tucker S, et al. ESHAP—an effective
chemotherapy regimen in refractory and relapsing lymphoma: a 4‐
year follow‐up study. J Clin Oncol. 1994;12:1169‐1176.
45. Skamene T, Crump M, Savage KJ, et al. Salvage chemotherapy and
autologous stem cell transplantation for peripheral T‐cell lymphoma:
a subset analysis of the Canadian Cancer Trials Group LY.12 ran-
domized phase 3 study. Leuk Lymphoma. 2017;58(10):2319‐2327.
https://doi.org/10.1080/10428194.2017.1312379
46. Kharfan‐Dabaja MA, Kumar A, Ayala E, et al. Clinical practice rec-
ommendations on indication and timing of hematopoietic cell
transplantation in mature T cell and NK/T cell lymphomas: an in-
ternational collaborative effort on behalf of the guidelines commit-
tee of the American Society for Blood and Marrow Transplantation.
Biol Blood Marrow Transplant. 2017;23(11):1826‐1838. https://doi.
org/10.1016/j.bbmt.2017.07.027
47. Loirat M, Chevallier, P, Leux C, et al. Upfront allogeneic stem‐cell
transplantation for patients with nonlocalized untreated peripheral
LUMINARI AND SKRYPETS
-
59
T‐cell lymphoma: an intention‐to‐treat analysis from a single center.
Ann Oncol. 2015;26(2):386‐392.
48. Kyriakou C, Canals C, Finke J, et al. Allogeneic stem cell
transplantation is able to induce long‐term remissions in
angioimmunoblastic T‐cell lymphoma: a retrospective study from
the lymphoma working party of the European group for blood
and marrow transplantation. J Clin Oncol. 2009;27(24):
3951‐3958.
49. Smith SM, Burns LJ, van Besien K, et al. Hematopoietic cell trans-
plantation for systemic mature T‐cell non‐Hodgkin lymphoma. J Clin
Oncol. 2013;31(25):3100‐3109.
50. O'Connor OA, Falchi L, Lue JK, et al. Oral 5‐azacytidine and romi-
depsin exhibit marked activity in patients with PTCL: a multicenter
phase 1 study. Blood. 2019;134(17):1395‐1405. https://doi.org/10.
1182/blood.2019001285
51. Horwitz SM, Feldman TA, Hess BT, et al. The novel SYK/JAK in-
hibitor cerdulatinib demonstrates good tolerability and clinical
response in a phase 2a study in relapsed/refractory peripheral T‐cell
lymphoma and cutaneous T‐cell lymphoma. Blood. 2018;132(sup-
plement 1):1001. https://doi.org/10.1182/blood‐2018‐99‐119944
52. Horwitz SM, Koch R, Porcu P, et al. Activity of the PI3K‐δ,γinhibitor
duvelisib in a phase 1 trial and preclinical models of T‐cell
lymphoma. Blood. 2018;131(8):888‐898. https://doi.org/10.1182/
blood‐2017‐08‐802470
53. Lesokhin AM, Ansell SM, Armand P, et al. Nivolumab in patients with
relapsed or refractory hematologic malignancy: preliminary results
of a phase Ib study. J Clin Oncol. 2016;34(23):2698‐2704. https://doi.
org/10.1200/JCO.2015.65.9789
54. Maciocia PM, Wawrzyniecka PA, Philip B, et al. Targeting the T cell
receptor β‐chain constant region for immunotherapy of T cell ma-
lignancies. Nat Med. 2017;23(12):1416‐1423. https://doi.org/10.
1038/nm.4444
55. Sawas A, Elgedawe H, Vlad G, et al. Clinical and biological evaluation
of the novel CD30/CD16A tetravalent bispecific antibody (AFM13)
in relapsed or refractory CD30‐positive lymphoma with cutaneous
presentation: a biomarker phase Ib/IIa study (NCT03192202). Blood.
2018;132(supplement 1):2908.
How to cite this article: Luminari S, Skrypets T. What's new in
peripheral T‐cell lymphomas. Hematological Oncology.
2021;39(S1):52–60. https://doi.org/10.1002/hon.2846
60
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LUMINARI AND SKRYPETS
Received: 26 February 2021
DOI: 10.1002/hon.2854
SUPPLEMENT ARTICLE
Recognizing but not harming. Borderline B‐cell lymphoid
proliferations
Leticia Quintanilla‐Martinez
Institute of Pathology and Neuropathology,
Eberhard Karls University of Tübingen and
Comprehensive Cancer Center, Tübingen
University Hospital, Tübingen, Germany
Correspondence
Leticia Quintanilla‐Martinez, Institute of
Pathology, University Hospital Tübingen
Liebermeisterstrasse 8, 72076 Tübingen,
Germany.
Email: Leticia.quintanilla-fend@med.uni-
tuebingen.de
Funding information
Open access funding was enabled and
organized by Projekt DEAL.
Abstract
In the last years several borderline B‐cell lymphoid proliferations have been recog-
nized that lie at the interface between benign and malignant. These lesions can be
divided in two groups; those considered precursor lesions of well recognized lymphoid
malignancies and the group of indolent lymphomas with limited potential for pro-
gression. Precursor lesions are monoclonal and share many genetic features of their
malignant counterpart. The first recognized precursor lesion was monoclonal
gammopathy of undetermined significance. Thereafter, the widespread use of
immunohistochemistry, fluorescence‐activated cell sorting analysis and molecular
techniques in lymphoid samples led to the recognition of other precursor lesions such
as monoclonal B‐cell lymphocytosis, in situ follicular neoplasia and in situ mantle cell
neoplasia. The second group of disorders comprises monoclonal lymphoid pro-
liferations with limited malignant potential without a counterpart among the
currently recognized lymphoma entities; these include pediatric‐type follicular lym-
phoma, pediatric nodal marginal zone lymphoma, and duodenal‐type follicular lym-
phoma. Despite their clonal nature, a conservative treatment has been shown to be
sufficient in most cases. The diagnostic criteria of precursor/indolent B‐cell pro-
liferations, recent advances in the understanding of progression and lymphoma-
genesis and current recommendations for treatment will be discussed. In order to
avoid unnecessary and potentially harmful therapy, these lesions need to be recog-
nized and diagnosed correctly.
KEYWORDS
B‐cell lymphoma, early lesion, indolent lymphoma, precursor lesion
1
|
INTRODUCTION
The paradigm that invasive cancer is frequently preceded by pre-
malignant lesions has been proven in solid tumors. However, this
concept is difficult to apply to lymphoid neoplasms because lym-
phocytes due to their innate properties recirculate through different
lymphoid tissues and organs based on the patterns of normal
lymphocyte homing.
1
The increasing use of immunohistochemistry, fluorescence‐
activated cell sorting (FACS) analysis and molecular techniques on
lymphoid tissue samples has led to the identification of a number of
borderline B‐cell lymphoid proliferations between benign and
This is an open access article under the terms of the Creative Commons Attribution‐NonCommercial‐NoDerivs License, which permits use and distribution in any
medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.
© 2021 The Authors. Hematological Oncology published by John Wiley & Sons Ltd.
Hematological Oncology. 2021;39(S1):61–67. wileyonlinelibrary.com/journal/hon
-
61
malignant.
1
Some of these lesions represent precursor lesions and
some clonal lymphoid proliferations with limited malignant potential
(Table 1). The precursor lymphoid proliferations are often incidental
findings in asymptomatic individuals with mostly indolent biological
behavior. Importantly, these lymphoid proliferations are monoclonal
and carry many of the molecular features of their malignant coun-
terpart such as the t(14;18) and t(11;14) translocations associated to
in situ follicular neoplasia (ISFN) and in situ mantle cell neoplasia
(ISMCN), respectively. Other B‐cell proliferations with low risk of
progression include monoclonal B‐cell lymphocytosis (MBL) of
chronic lymphocytic leukemia (CLL)‐type and the non‐CLL type. In
pediatric and young populations two clonal B‐cell proliferations with
apparently no risk of progression are recognized including pediatric‐
type follicular lymphoma (PTFL) and pediatric nodal marginal zone
lymphoma (PMZL). There are some lymphoid proliferations that
home to specific anatomic sites and remain localized such as
duodenal‐type follicular lymphoma (DFL).
2
|
PRECURSOR LESIONS IN B‐CELL
LYMPHOMAGENESIS
2.1
|
Monoclonal gammopathy of undetermined
significance
Monoclonal gammopathy of undetermined significance (MGUS) is the
paradigmatic example for the clonal evolution of lymphoid neo-
plasms.
2
It is defined as a serum monoclonal protein less than 3 g/dl,
less than 10% monoclonal plasma cells in the bone marrow (BM) and
absence of SLiM‐CRAB criteria (≥60% clonal plasma cells, free light
chain (FLC) ratio ≥100, >1 focal lesion on magnetic resonance im-
aging, hypercalcemia, renal insufficiency, anemia and lytic bone le-
sions). MGUS is a premalignant clonal disorder that progresses at a
rate of 1% per year. The incidence of MGUS increases with age
affecting 3%–4% individuals ≥50 years and 5% at ≥70 years. It is
classified based on the involved immunoglobulin (IG) in IGM, non‐
IGM and light chain types. Non‐IGM MGUS might progress to mul-
tiple myeloma (MM), solitary plasmacytoma or amyloid light chain
disease, whereas IGM MGUS has an increased risk to progress to
Waldeström macroglobulinemia (WM) or CLL. Interestingly, MGUS,
smoldering MM (SMM) and MM share cytogenetic alterations
including major translocations involving the IGH gene and numerical
chromosomal abnormalities (CNAs). Nevertheless, there seems to be
a temporal acquisition of CNAs, some of which are more prevalent at
later stages such as del13q, indicating that they may be secondary
events. Similarly, although t(11;14) is observed in MGUS and MM, t
(4;14) and t(14;16) are more common in SMM and MM. MGUS has a
less complex genomic landscape carrying rarely MM‐associated so-
matic mutations. Furthermore, MYC translocations and TP53 de-
letions and mutations are not observed in MGUS, suggesting that
these are drivers of progression. The most common CNAs for IGM
MGUS/WM are del6q, +18q, trisomy 4, 5, 12, and monosomy 8. The
most frequent mutation is MYD88 L265P, followed by mutations in
CXCR4 and KMT2D, akin to manifest WM.
A major advance in the understanding of MM pathogenesis was
the recognition of the dynamic interaction between the tumor cells
TABLE 1Precursor/indolent lesions
in lymphoid neoplasias
Precursor lesions phenotypically and genotypically similar to malignant counterpart
Monoclonal gammopathy of undetermined significance
Monoclonal B‐cell lymphocytosis
‐Chronic lymphocytic leukemia (CLL) type
‐Atypical CLL type
‐Non‐CLL type
In situ follicular neoplasia
In situ mantle cell neoplasia
Clonal lymphoid proliferations of limited malignant potential (B and T)
Duodenal‐type follicular lymphoma
Pediatric‐type follicular lymphoma
Pediatric nodal marginal zone lymphoma
Primary cutaneous marginal zone lymphoma
Primary cutaneous acral CD8+T‐cell lymphoma
Primary cutaneous CD4+T‐cell lymphoproliferative disorder (LPD)
Indolent T‐cell LPD of the gastrointestinal tract
Lymphomatoid papulosis
62
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QUINTANILLA‐MARTINEZ
and the surrounding microenvironment. The permissive BM micro-
environment favors clonal selection and progression from MGUS to
MM. The BM microenvironment seems to exert a selective pressure
that promotes the expansion of subclones with selective advantage
and facilitates progression to symptomatic disease. Additionally, the
immunosuppressive BM microenvironment through expansion of
regulatory T‐cells and T‐helper 17 cells determines whether MGUS
remains stable or progresses to MM.
There are several risk stratification models to predict MGUS
progression. The most widely used is the “Mayo Clinic model”: (1) M‐
protein greater than 1.5 g/dl, (2) non‐IgG isotype, and (3) FLC ratio
less than 0.26 or more than 1.65, which stratifies patients from low to
high risk. High risk patients have all three risk factors and a 20‐years
progression risk of 58%. Currently, there is no recommended treat-
ment for MGUS except for careful monitoring for progression to
enable early detection and intervention.
3
An exception is what has
been called “MGCS.” This refers to patients with MGUS criteria but
experiencing symptoms and signs related to the nerves, skin and
kidney causing serious disease. Treatment recommendations include
IV IG, rituximab, and plasma cell‐directed therapy.
4
There are
promising clinical trials investigating different therapeutic strategies
to prevent progression from high‐risk MGUS to symptomatic disease
including a phase II trial with daratumumab.
3
Introduction of novel
therapies that seem to be both safe and effective are challenging the
belief that MM should only be treated when symptomatic.
2.2
|
Monoclonal B‐cell lymphocytosis
MBL is defined as a monoclonal B‐cell count less than 5000/μl in
peripheral blood (PB), persisting for at least 3 months in otherwise
asymptomatic individuals.
5
Based on its clinical significance, MBL is
divided into high‐count (500–5000/µl) and low‐count MBL (<500/
µl); the latter without risk to develop CLL, and therefore, no
follow‐up is required. MBL is classified into three categories based
on its phenotype: (1) CLL type, (2) atypical‐CLL type, and (3) non‐
CLL type.
(1) MBL of CLL type is the most common (75%), and has an identical
phenotype to CLL (CD19+, CD20dim, CD23+, CD5+, LEF1+).
Among healthy individuals, MBL has a reported incidence be-
tween 3% and 12%, depending on the age. CLL is always pre-
ceded by MBL, which is considered a premalignant condition
with a progression rate to CLL of 1%–2% per year; however, only
a minority of MBL cases will eventually progress into CLL.
1
The
number of MBL cells at presentation seems to be the highest risk
factor for progression. It is now well established that progression
from MBL to CLL is due to the combined effect of genetic defects
and its interaction with the microenvironment.
1
MBL cases
usually have mutated IGHV, and carry the same genetic alter-
ations as seen in CLL including del13q, trisomy 12, del11q, and
del17p, although at lower levels suggesting that these changes
occur early in clonal evolution. Point mutations in TP53,
NOTCH1,ATM, and SF3B1 genes are also detected in MBL but
mostly as subclones.
6,7
Current recommendations include yearly
monitoring for early intervention if clinically indicated.
(2) MBL with atypical CLL phenotype shows CD20 bright by FACS
analysis and often is CD23 negative but express CD5. The pos-
sibility of a mantle cell lymphoma (MCL) should be excluded.
(3) MBL of non‐CLL type is characterized by CD20+, CD19+B cells
with moderate to bright surface IG expression but CD5 nega-
tivity (or CD5 dim in 20% of cases), a phenotype that has been
related to marginal zone (MZ) lymphoma. In PB the lymphocytes
show a broad cytological spectrum with variable numbers of
villous lymphocytes and lymphocytes with plasmacytoid differ-
entiation. BM biopsy shows always B‐cell infiltrations of various
degrees. Most patients remain stable without progression but
around 17% will develop splenomegaly and laboratory findings
suggestive of splenic MZ lymphoma or splenic B‐cell lymphoma
unclassifiable. The term CBL‐MZ origin has been proposed.
8
The
immunogenetic signature of these cases is strongly indicative of
antigen selection with highly mutated IG genes (76%) and pre-
dominance of the IGHV4‐34 gene (23%). Up to 23% of the cases
show complex karyotype with frequent del7q and isochromo-
some 17q. Mutational analysis is limited to few cases; however,
NOTCH2 (13%), TNFAIP3 (6%), and CD79B (6%) gene mutations
have been described.
9
Interestingly, MYD88 mutations were
identified in 25% of cases, especially those cases secreting IGM;
the differential diagnosis with WM is mandatory. Accordingly, it
is recommended to evaluate individuals at diagnosis with
detailed immunophenotype, cytogenetics (fluorescence in situ
hybridization), MYD88 gene mutation screening and imaging. The
role of BM biopsy at diagnosis is debatable since there is no
correlation between the extent of BM and PB infiltration. Long
follow‐up is recommended but treatment should only be
considered in cases with evidence of progression.
2.3
|
In situ follicular neoplasia
FL is the second most common B‐cell lymphoma in adults and ac-
counts for about 20% of all lymphomas. Most patients have wide-
spread disease at diagnosis with BM involvement in 40%–70% of the
cases. FL cells acquire resistance against apoptosis through the
chromosomal translocation t(14;18)/BCL2/IGH present in around
85% of the cases. Using immunohistochemistry and highly sensitive
molecular techniques two putative FL precursor forms have been
identified.
10
(1) FL‐like B cells carrying the t(14;18) translocation can
be identified in the PB in up to 55% of healthy individuals. These
cells increase with age, smoking, and exposure to pesticides. Most
t(14;18)‐positive clones are long‐lived and can persist for several
years, indicating that the deregulated BCL2 expression is not suffi-
cient for the development of manifest (m)FL. FL‐like B cells have high
levels of somatic hypermutation (SHM) and class switch recombina-
tion (CSR) suggestive of intense trafficking in the germinal center
(GC). Importantly, patients who develop mFL seem to have a higher
QUINTANILLA‐MARTINEZ
-
63
number of circulating FL‐like B‐cells many years before the diagnosis
of mFL compared with controls.
(2) ISFN is a precursor lesion considered to be a tissue manifes-
tation of FL‐like B cells, which show the genetic and immunopheno-
typic features of FL, but localized to the GC of reactive‐appearing
lymph nodes (LN) (Figure 1). ISFN can only be identified by BCL2
immunostain, is monoclonal and carries the t(14;18) translocation. The
incidence of ISFN is unknown, but studies of unselected LNs from
adults revealed a prevalence of 2%, and the rate for progression to mFL
has been estimated to be between 2% and 3%. Nevertheless, because
15%–20% of ISFN cases are diagnosed in a LN involved by another B‐
cell lymphoma (not only FL), it is recommended to have complete
staging workup, including imaging studies and BM biopsy to rule out
concurrent lymphoma. No treatment is needed.
11
ISFN represents a FL precursor lesion with no or few CNAs.
11
Nevertheless ISFN shares many genetic features with mFL including
early introduction of N‐glycosylation sites substituting conventional
antigen binding favoring the generation of long‐lived clones and
increasing the chances of secondary hits. Accordingly, ISFN carry
mutations in CREBBP,EZH2,TNFRSF14, and KMT2D but at lower
frequencies when compared to paired mFL.
12
The putative model of FL
lymphomagenesis suggests that the t(14;18) is the first hit resulting
from a repair error during the IGH variable diversity joining region
recombination process in the BM leading to the accumulation of cells
that will undergo repetitive rounds of GC reaction, acquiring additional
hits by SHM and CSR (FL‐like B cells). These cells acquire functional N‐
glycosylation sites that will interact with M2‐polarized macrophages in
the GC that retain the cells in the GC (ISFN), demonstrating the
importance of the interaction of activated B‐cell receptor (BCR) and its
microenvironment. These cells will undergo clonal expansion and
evolution with acquisition of CNAs and chromatin modifier gene mu-
tations necessary for final transformation into mFL. In contrast to
MGUS and MBL, there are no predictive biomarkers available to know
which individuals will progress from ISFN to mFL.
2.4
|
In situ mantle cell neoplasia
MCL represents around 6%–9% of all B‐cell lymphomas. At diagnosis
most patients present with disseminated disease with frequent
FIGURE 1 Precursor lesions in B‐cell lymphomas. In situ mantle cell neoplasia. (A) Panoramic view of a normal‐appearing lymph node
(hematoxylin and eosin [H&E], �25). (B) Cyclin D1 highlights the presence of cyclin D1+cells in the inner cuff of the mantle zone
(immunohistochemistry, �25). (C) The cells are also positive for the transcription factor SOX11 (immunohistochemistry, �200). (D) Higher
magnification demonstrates a specific nuclear staining for cyclin D1 (immunohistochemistry, �200). Insert: Fluorescence in situ hybridization
(FISH) analysis using a CCND1 break‐apart probe (BAP) demonstrates one normal colocalized signal (yellow arrow) and two separate signals
(red and green arrows) indicative of a translocation. In situ follicular neoplasia. (E) Panoramic view of a lymph node stain with H&E showing
normal architecture (original magnification, �25). (F) BCL2 stain shows that several germinal centers are replaced by lymphoid cells with
strong BCL2 expression (immunohistochemistry, �25). Insert: FISH analysis using a BCL2 BAP demonstrates one normal colocalized signal
(yellow arrow) and two separate signals (red and green arrows) indicative of a translocation. (G) The cells are strongly positive for CD10.
(H) MIB1 stain shows an abnormally low proliferation in the upper follicle with a normal polarized proliferation in the lower follicle. (I) BCL2
stain shows the abnormal expression of BCL2 in the upper follicle, stronger than the normal B cells of the mantle zone and reactive T cells. In
contrast in the lower follicle the germinal center remains BCL2 negative (G–I, immunohistochemistry, �200)
64
-
QUINTANILLA‐MARTINEZ
infiltration of the gastrointestinal tract and BM. MCL is characterized
by the t(11;14)/CCND1/IGH translocation in more than 90% of cases
with the residual 10% showing mostly cryptic CCND2/IG or CCND3/
IG translocations.
6
The phenotype includes the expression of B‐cell
markers (CD19, CD20) together with expression of CD5 and
SOX11 in most nodal cases. Rare cells with t(11;14) translocation
have been detected in up to 7% of healthy individuals in PB con-
firming that the CCND1‐IGH translocation is an early event in mantle
cell lymphomagenesis. MCL‐like cells and ISMCN are seen at a
significantly lower frequency than precursor lesions in FL. ISMCN is a
rare incidental finding in lymphoid tissue (<1%) characterized by the
presence of atypical cyclin D1+cells located within the 3–5 inner
layers of the mantle cuffs in an otherwise normal LN (Figure 1).
ISMCN is less characterized than ISFN; however, these two precur-
sor lesions seem to have in common the dependency on activated
BCR and the interaction with the microenvironment crucial for
homing to their natural niche.
1
The prolonged and repeated antigen
stimulation is believed to trigger the accumulation of genetic and
epigenetic aberrations in the MCL precursor cells, which eventually
progress to an overt lymphoma. Current recommendations include
staging with imaging and BM biopsy to rule out a concurrent overt
lymphoma. No treatment is required and follow‐up is advised. The
risk to progression is unknown.
3
|
INDOLENT LOCALIZED B‐CELL LYMPHOMAS
3.1
|
Duodenal‐type follicular lymphoma
DFL is a FL variant with unique clinical features. Patients present
with small polypoid lesions confined to the mucosa and submucosa
often in the region of the ampulla of Vater but can also involve
jejunum, ileum, and even colon. The clinical course is indolent with a
risk of progression and dissemination of about 3%. The overall sur-
vival at 10 years is 100% with limited or no treatment. The diagnosis
of DFL is often incidental and detected upon endoscopy for other
unrelated causes.
13
Histologically, the lesion is characterized by well
circumscribed follicles composed almost entirely by centrocytes that
also infiltrate the lamina propria with the same phenotype as FL
(CD10+, BCL2+, and BCL6+) (Figure 2). Some studies have shown
disrupted follicular dendritic cell meshworks and reduced or lack
activation‐induced deaminase expression compared to nodal FL. DFL
is monoclonal and carries the t(14;18) translocation. The expression
of α4β7 integrin by the tumor cells seem to be responsible for the
peculiar homing of these cells to the intestinal mucosa, a homing
receptor observed in mucosa‐associated lymphoid tissue lymphomas.
Similar to ISFN, DFL has low genomic complexity with frequent
mutations in CREBBP,TNFRSF14,KMT2D, and EZH2. Multiple KMT2D
mutations as seen in advanced FL are absent. Gene expression
profiling suggested that the immune microenvironment of DFL is
distinct from nodal FL and characterized by a chronic inflammatory
signature relevant to the pathophysiology of this disease. DFL and
ISFN are considered early/precursor lesions, clinically indolent with
low risk of progression. In fact DFL most probably represents a form
of in situ FL of the gastrointestinal tract. The Lugano staging system
is recommended to evaluate the potential of progression. If nodal
involvement is present (Stage II) there is a higher rate of progression.
DFL should be distinguished from conventional FL with intestinal
involvement. In such cases, mesenteric LN involvement is often
present. There is no significant difference in survival or time to
progression between treated and untreated patients, which supports
the view that “watch and wait” strategy is preferred to therapeutic
intervention.
14
3.2
|
Pediatric‐type follicular lymphoma
PTFL is a FL variant that differs clinically, morphologically, and
genetically from the adult counterpart. Although this lymphoma
predominates in children and adolescents, similar cases have been
described in adults.
15
PTFL is recognized as an indolent disease
affecting predominantly young males (M:F ratio of 20:1) with a me-
dian age of 15 years, and presenting with isolated lymphadenopathy
in the head and neck regions.
16
Morphologically, it is characterized by
partial or total LN effacement by expansile, serpiginous follicles with
a prominent “starry‐sky” pattern but without polarization. In some
cases, evidence of MZ differentiation may be seen in the periphery of
the neoplastic follicles. The cells within the follicles show high‐grade
cytology (Grade 3) and express strongly CD10 and BCL6. BCL2
expression is usually absent, but around 20% of the cases show weak
positivity. PTFL is always monoclonal, which is required for the
diagnosis to exclude “atypical” follicular hyperplasia. The tumor cells
lack the characteristic t(14;18)/BCL2/IGH translocation of conven-
tional FL. Overall, PTFL lacks mutations of histone modifying genes
frequently found in FL and shows low levels of genomic complexity.
17
Recurrent genetic alterations of potential importance for its patho-
genesis that disrupt pathways associated with the GC reaction
(TNFRSF14,IRF8), immune escape (TNFRSF14) and anti‐apoptosis
(MAP2K1) have been described.
15,18
Complete staging involving BM
biopsy and lumbar puncture is standard care for children. Most pa-
tients presenting with localized disease have an excellent response
with surgery alone (completed resected lesion) without further
therapy. The actual recommendation is “watch and wait” after
resection. For patients with limited stage disease without complete
resection two to four courses chemotherapy according to protocols
for children with mature B‐cell lymphomas is the standard of care.
Relapses are very rare. The overall survival of children and adoles-
cents with PTFL is 100% in all published series.
19
3.3
|
Pediatric nodal MZ lymphoma
PMZL is uncommon and shows remarkably overlapping clinical and
pathological features with PTFL. It is more common in males under
18 years of age and presents as asymptomatic isolated lymphade-
nopathy commonly in the head and neck region. Histologically,
QUINTANILLA‐MARTINEZ
-
65
residual follicles in PMZL are often present and show fragmentation
due to infiltration of the mantle cells into the remaining GC resem-
bling progressive transformation of germinal centers (PTGC). The
mantle zone is expanded and can be highlighted by IgD staining,
which in addition, emphasizes the PTGC‐like changes. In contrast to
PTFL, there is interfollicular infiltration of CD10‐, BCL6‐tumor cells
and diffuse areas. Staining for CD279/PD1 shows numerous cells in
the reactive GCs, a feature that is useful in the differential diagnosis
with PTFL. Monoclonality is detected in all cases. No recurrent mu-
tations have been identified. These cases show low levels of genomic
complexity with few genetic aberrations such as trisomy 18 and tri-
somy 3. Similar to PTFL a “watch and wait” strategy is recommended
after resection.
19
4
|
CONCLUSIONS
The precursor lesions discussed here have unique clinical, morpho-
logical, immunophenotypical, and genetic features. Nevertheless,
MBL, ISFN, and ISMCN share some biological features, such as
dependency on BCR activation and the important interaction with
the microenvironment. These precursor lesions can be detected in
healthy individuals and in general have a low risk of progression to a
malignant lymphoma. The complex interplay between genetic alter-
ations, BCR activation and microenvironment seems to be respon-
sible for progression to an overt lymphoma. Patients with these
precursor lesions should be staged at diagnosis but treatment is
recommended only if progression occurs, although this dogma might
change in the future. Indolent lymphomas such as DFL, PTFL, and
PMZL represent challenging diagnoses sometimes difficult to sepa-
rate from reactive conditions. The understanding and definition of
these disorders have increased tremendously in the last 5 years. For
PTFL and PMZL complete surgical resection followed by “watch and
wait” strategy seems an adequate therapy with low‐intensity
chemotherapy restricted to incompletely resected disease. Finally,
the most important take home message is to recognize these lesions
and avoid unnecessary and potentially harmful therapy.
ACKNOWLEDGMENTS
Open access funding was enabled and organized by Projekt DEAL.
FIGURE 2 Duodenal‐type follicular lymphoma. (A) Aggregates of neoplastic follicles mainly restricted to the duodenal mucosa
(hematoxylin and eosin [H&E], snap‐shot of a scanned slide). (B) Strong and homogeneous CD20 positivity in the follicular structures and in the
lamina propria (immunohistochemistry, snap‐shot of a scanned slide). (C) At higher magnification the follicles are replaced by mainly
centrocyte‐like cells (Grade 1) (H&E, �100). (D) CD23 stain highlights the abnormal distribution of follicular dendritic cells in the periphery of
the neoplastic follicles (immunohistochemistry, �100) The tumor cells are positive for (E) BCL2, (F) BCL6, (G) and CD10
(immunohistochemistry, �50)
66
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QUINTANILLA‐MARTINEZ
CONFLICT OF INTERESTS
The author declares that there is no conflict of interests.
PEER REVIEW
The peer review history for this article is available at https://publons.
com/publon/10.1002/hon.2854.
REFERENCES
1. Ghia P, Nadel B, Sander B, Stamatopoulos K, Stevenson FK. Early
stages in the ontogeny of small B‐cell lymphomas: genetics and
microenvironment. J Intern Med. 2017;282(5):395‐414.
2. Mouhieddine TH, Weeks LD, Ghobrial IM. Monoclonal gammopathy
of undetermined significance. Blood. 2019;133(23):2484‐2494.
3. Ho M, Patel A, Goh CY, Moscvin M, Zhang L, Bianchi G. Changing
paradigms in diagnosis and treatment of monoclonal gammopathy of
undetermined significance (MGUS) and smoldering multiple
myeloma (SMM). Leukemia. 2020;34(12):3111‐3125.
4. Dispenzieri A. Monoclonal gammopathies of clinical significance.
Hematology Am Soc Hematol Educ Program. 2020;2020(1):380‐388.
5. Marti GE, Rawstron AC, Ghia P, et al. Diagnostic criteria for mono-
clonal B‐cell lymphocytosis. Br J Haematol. 2005;130(3):325‐332.
6. Puente XS, Jares P, Campo E. Chronic lymphocytic leukemia and
mantle cell lymphoma: crossroads of genetic and microenvironment
interactions. Blood. 2018;131(21):2283‐2296.
7. Ojha J, Secreto C, Rabe K, et al. Monoclonal B‐cell lymphocytosis is
characterized by mutations in CLL putative driver genes and clonal
heterogeneity many years before disease progression. Leukemia.
2014;28(12):2395‐2398.
8. Xochelli A, Kalpadakis C, Gardiner A, et al. Clonal B‐cell lymphocy-
tosis exhibiting immunophenotypic features consistent with a
marginal‐zone origin: is this a distinct entity?. Blood. 2014;123(8):
1199‐1206.
9. Bruscaggin A, Monti S, Arcaini L, et al. Molecular lesions of signalling
pathway genes in clonal B‐cell lymphocytosis with marginal zone
features. Br J Haematol. 2014;167(5):718‐720.
10. Mamessier E, Broussais‐Guillaumot F, Chetaille B, et al. Nature and
importance of follicular lymphoma precursors. Haematologica.
2014;99(5):802‐810.
11. Schmidt J, Salaverria I, Haake A, et al. Increasing genomic and
epigenomic complexity in the clonal evolution from in situ to
manifest t(14;18)‐positive follicular lymphoma. Leukemia. 2014;
28(5):1103‐1112.
12. Schmidt J, Ramis‐Zaldivar JE, Bonzheim I, et al. CREBBP gene mu-
tations are frequently detected in in situ follicular neoplasia. Blood.
2018;132(25):2687‐2690.
13. Hellmuth JC, Louissaint A, Jr., Szczepanowski M, et al. Duodenal‐
type and nodal follicular lymphomas differ by their immune micro-
environment rather than their mutation profiles. Blood. 2018;
132(16):1695‐1702.
14. Schmatz AI, Streubel B, Kretschmer‐Chott E, et al. Primary follicular
lymphoma of the duodenum is a distinct mucosal/submucosal
variant of follicular lymphoma: a retrospective study of 63 cases.
J Clin Oncol. 2011;29(11):1445‐1451.
15. Louissaint A, Jr., Schafernak KT, Geyer JT, et al. Pediatric‐type nodal
follicular lymphoma: a biologically distinct lymphoma with frequent
MAPK pathway mutations. Blood. 2016;128(8):1093‐1100.
16. Liu Q, Salaverria I, Pittaluga S, et al. Follicular lymphomas in children
and young adults: a comparison of the pediatric variant with usual
follicular lymphoma. Am J Surg Pathol. 2013;37(3):333‐343.
17. Schmidt J, Gong S, Marafioti T, et al. Genome‐wide analysis of
pediatric‐type follicular lymphoma reveals low genetic complexity
and recurrent alterations of TNFRSF14 gene. Blood. 2016;128(8):
1101‐1111.
18. Schmidt J, Ramis‐Zaldivar JE, Nadeu F, et al. Mutations of MAP2K1
are frequent in pediatric‐type follicular lymphoma and result in ERK
pathway activation. Blood. 2017;130(3):323‐327.
19. Woessmann W, Quintanilla‐Martinez L. Rare mature B‐cell lym-
phomas in children and adolescents. Hematol Oncol. 2019;37(Suppl
1):53‐61.
How to cite this article: Quintanilla‐Martinez L. Recognizing
but not harming. Borderline B‐cell lymphoid proliferations.
Hematological Oncology. 2021;39(S1):61–67. https://doi.org/
10.1002/hon.2854
QUINTANILLA‐MARTINEZ
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Received: 15 February 2021
DOI: 10.1002/hon.2848
SUPPLEMENT ARTICLE
Sequencing of myeloma therapy: Finding the right path
among many standards
S. Vincent Rajkumar
Division of Hematology, Mayo Clinic, Rochester, Minnesota, USA
Correspondence
S. Vincent Rajkumar, Division of Hematology, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA.
Email: rajkumar.vincent@mayo.edu
In the last decade, major changes have occurred in the diagnostic
criteria, staging system, and response criteria for multiple myeloma
(MM).
1,2
These changes have been accompanied by several advances
in treatment of the MM, including many new drugs (carfilzomib,
pomalidomide, daratumumab, elotuzumab, panobinostat, ixazomib,
selinexor, isatuximab, and belantamab). Numerous clinical trials
provide data on best practices along the spectrum of the disease. The
purpose of this article is to describe the complexity of MM therapy in
a landscape where many parallel standards exist for the same
indications, and to provide an outline selecting the first line and
subsequent sequencing of therapy according to dynamic changes in
the disease and patient features.
1
|
INTIAL THERAPY
Approach to initial therapy in myeloma is affected by host factors
(age, performance status, renal function), eligibility for stem cell
transplantation, and presence or absence of high risk features. High‐
risk MM is defined by the presence of t(4;14), t(14;16), t(14;20),
deletion 17p, gain 1q, or p53 mutation.
3
Double‐hit MM refers to the
presence of any two or more high‐risk abnormalities. Triple‐hit MM
refers to the presence of three or more high‐risk abnormalities.
Although minimal residual disease (MRD) negative status is associ-
ated with improved progression‐free survival (PFS) and overall
survival (OS), there are no data from randomized trials that
modifying therapy in MRD positive patients in an attempt to make
them MRD negative will lead to better outcomes.
The current algorithms for the treatment of symptomatic newly
diagnosed MM is shown in Figure 1. Patients who candidates for
autologous stem cell transplantation (ASCT) are treated with three to
four cycles of induction therapy followed by stem cell harvest. After
stem cell harvest, the standard of care has been ASCT followed by
maintenance. However, in selected patients who have standard risk
MM, ASCT can be delayed until relapse, and randomized trials show
no detrimental effect on OS with such an approach.
The preferred initial therapy is bortezomib, lenalidomide, and
dexamethasone (VRd).
4
The 4‐year OS rate with VRd is greater than
80% with or without early ASCT.
5
An important alternative to VRd
in newly diagnosed MM is daratumumab, lenalidomide, and
dexamethasone (DRd). DRd has shown significant efficacy in a
randomized trial conducted in transplant ineligible patients, with
improved PFS compared with Rd.
6
However, there are important
differences between the two approaches, particularly in transplant
ineligible patients where VRd consists of triplet therapy for 6 months
followed by maintenance, while DRd requires continuous triplet
therapy until disease progression. Thus due to overall cost, and
strength of long‐term data, I prefer VRd over DRd for most patients.
7
However, DRd is a suitable alternative for patients with preexisting
neuropathy or for patients who have intolerance to VRd. In high‐risk
transplant eligible patients with double hit MM or triple hit MM,
I recommend addition of daratumumab to the standard VRd regimen
(Dara‐VRd), or the daratumumab, bortezomib, thalidomide, and
dexamethasone (Dara‐VTd) regimen.
8
There is no significant benefit
with carfilzomib, lenalidomide, and dexamethasone (KRd) over VRd in
newly diagnosed MM.
9
KRd is more expensive, and is associated with
a higher risk of serious cardiac, renal, and pulmonary toxicity
than VRd.
In certain settings, the treatment regimens for newly diagnosed
MM must be modified. Thus, bortezomib, cyclophosphamide, and
dexamethasone (VCd) is the preferred regimen in patients presenting
with acute renal failure due to light chain cast nephropathy. In
patients with primary plasma‐cell leukemia multiagent combination
chemotherapy such as bortezomib/dexamethasone/thalidomide/
cisplatin/doxorubicin/cyclophosphamide/etoposide (VDT‐PACE) is
usually needed initially to achieve rapid disease control. In elderly
frail patients who are unable to travel to receive parenteral therapy,
the all oral regimen of ixazomib, lenalidomide, and dexamethasone
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Hematological Oncology. 2021;39(S1):68–72. wileyonlinelibrary.com/journal/hon © 2021 John Wiley & Sons Ltd.
(Ixa‐Rd) is a reasonable alternative to VRd and DRd. Melphalan‐
based regimens are no longer recommended for newly diagnosed
MM due to concerns about stem cell damage, secondary myelodys-
plastic syndrome, and acute leukemia.
1.1
|
Timing of stem cell transplantation
One of the main controversies in initial therapy is concerning the
sequencing of ASCT. Older randomized trials have found similar OS
with early ASCT (immediately following four cycles of induction
therapy) versus delayed ASCT (at the time of relapse as salvage
therapy). More recently, the Intergroupe Francophone du Myelome
(IFM) trial found no significant OS difference between early versus
delayed ASCT in patients treated with VRd as initial therapy and
lenalidomide maintenance.
10
No difference has emerged even after
8 years of follow‐up. There is a significant improvement in PFS as
expected with early ASCT, and there are other logistical benefits to
ASCT. In general, early ASCT is preferred, but based on the IFM
results it is reasonable to consider a delayed ASCT in patients with
standard‐risk multiple MM who prefer such an approach for personal
reasons.
The role of consolidation therapy and tandem (double) ASCT
is limited. Results of randomized trials are contradictory and
likely reflect the availability of new treatment options in the
salvage setting. In the United States, where multiple options for
salvage therapy are available, there seems to be no benefit with
tandem ASCT. At present, outside of a clinical trial setting, we
consider tandem ASCT only in selected young patients with
del 17p.
FIGURE 1 Approach to the treatment of newly diagnosed myeloma in transplant eligible (A) and transplant ineligible (B) patients. ASCT,
autologous stem cell transplantation; Dara‐VRd, daratumumab, bortezomib, lenalidomide, dexamethasone; DRd, daratumumab, lenalidomide,
dexamethasone; VRd, bortezomib, lenalidomide, dexamethasone. Modified from Rajkumar and Kumar
2
RAJKUMAR
-
69
1.2
|
Maintenance therapy
The standard of care following initial therapy MM is lenalidomide
maintenance. In high‐risk patients, bortezomib plus lenalidomide, or
VRd maintenance is preferable. There are limited data on optimal
duration of maintenance. Many patients can benefit from a drug‐free
interval, and trials are examining if the duration of maintenance can
be modified based on MRD results.
1.3
|
Relapsed MM
MM is characterized by multiple remissions and relapses. The
sequencing of therapies appropriately is critical in achieving the best
long‐term survival. Many patients with MM receive five or more
lines of therapy in a sequential manner over several years. The
choice of treatment at each relapse is affected by the Timing of the
relapse, Response to prior therapy, Aggressiveness of the relapse,
and Performance status. Patients are eligible for ASCT should be
considered for transplantation if they had elected to delay the
procedure, or if they achieved excellent remission duration with the
first ASCT, defined as a remission of 36 months or longer with
maintenance.
In order to provide the best sequential therapy, we need to
select the most active regimen early on. A triplet regimen is preferred
at first relapse. At each subsequent relapse, a triplet, quadruplet, or
multidrug regimen that contains at least two new drugs that the
patient is not refractory to should be used. The algorithm for the
treatment of relapsed MM is given in Figure 2.
Treatment is typically continued until disease progression.
However, based on tolerability and response, increasing the interval
between cycles, as well as treatment‐free intervals should be
considered.
At first relapse, my preferred option is DRd for patients who are
not refractory to lenalidomide. If patients are refractory to lenali-
domide, the choices are daratumumab, bortezomib dexamethasone
FIGURE 2 Approach to the treatment of relapsed multiple myeloma in first relapse (A) and second or higher relapse (B). DKd,
daratumumab, carfilzomib, and dexamethasone; DPd, daratumumab, pomalidomide, and dexamethasone; DRd, daratumumab, lenalidomide,
and dexamethasone; DVd, daratumumab, bortezomib, and dexamethasone; ERd, elotuzumab, lenalidomide, and dexamethasone; IPd, ixazomib,
pomalidomide, and dexamethasone; IRd, ixazomib, lenalidomide, and dexamethasone; KPd, carfilzomib, pomalidomide, and dexamethasone;
KRd, carfilozomib, lenalidomide, and dexamethasone; VCd, bortezomib, cyclophosphamide. Modified from Rajkumar and Kumar
2
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RAJKUMAR
(DVd), daratumumab pomalidomide, dexamethasone, or isatuximab,
pomalidomide, dexamethasone. In patients who are refractory to
daratumumab at first relapse, carfilzomib‐based regimens such as
KRd or carfilzomib, pomalidomide, dexamethasone (KPd) are excel-
lent options. For patients who are frail, Ixa‐Rd would be a reasonable
first choice for relapse.
There are numerous other alternatives, and these can be used in
second and subsequent relapses. They include elotuzumab, pomali-
domide, dexamethasone (EPd), bortezomib, cyclophosphamide,
dexamethasone (VCd), bortezomib, pomalidomide, dexamethasone
(VPd), and daratumumab, carfilzomib, and dexamethasone (DKd).
Unfortunately, none of the triplet regimens used in relapsed MM
have been compared head‐to‐head in randomized trials.
When sequencing therapy, there are a few other important
considerations. At each relapse, any of the regimens that were
mentioned for use in first relapse can be considered, with the goal of
having at least two new drugs that the patient is not refractory two,
and preferably from a different drug class. In many instances, this
may mean the necessity of adding a monoclonal antibody to one of
the triplets to create a quadruplet regimen. Although it is in the same
drug class, pomalidomide has clinical activity in patients who are
refractory to lenalidomide. Similarly, carfilzomib has activity in
patients who are refractory to bortezomib. Carfilzomib is typically
administered twice‐weekly at a dose of 27 mg/m
2
, but a once‐weekly
schedule of 56–70 mg/m
2
may be equally effective and safe, and
more convenient.
11
Carfilzomib has a lower risk of neurotoxicity than
bortezomib, but approximately 5% of patients can experience serious
cardiac side effects.
1.4
|
Refractory myeloma
There are several additional options for patients with MM
refractory to immunomodulatory drugs, proteasome inhibitors,
alkylators, CD38 antibodies, and elotuzumab. One option is to add
panobinostat to a proteasome‐inhibitor containing regimen. A
second option is to use a selinexor‐containing regimen such as
selinexor, bortezomib, dexamethasone (SVd). A third options is
treatment with belantamab mafodotin, a humanized anti‐BCMA
antibody that is conjugated to monomethyl auristatin‐F, a micro-
tubule disrupting agent.
12
Other options for refractory disease
include bendamustine‐containing regimens or anthracycline‐
containing regimens.
Venetoclax is not approved for use in MM, but has single‐agent
activity in patients with t(11;14) subtype of MM.
13
A recent ran-
domized trial found significantly higher mortality with venetoclax in
relapsed MM despite producing deeper responses and better PFS.
14
Therefore, venetoclax is considered investigational, and its use
should be restricted to patients with t(11;14) who have relapsed
disease.
With careful analysis of the various options and combinations
possible, we can induce remissions multiple times with creative
strategies. At each step opportunities for clinical trials may open up
and should be considered.
1.5
|
Investigational treatments
One of the most exciting options being studied is chimeric antigen
receptor T cells targeting B cell maturation antigen such as bb2121.
15
In studies so far, more than 80% of patients appear to respond, with
median response duration of approximately 12 months. Another
promising new strategy is the use of bispecific T‐cell engager, such as
AMG 701, talquetamab, or cevostamab. Iberdomide and other
cereblon inhibitors are also showing promise.
ACKNOWLEDGMENTS
This study was supported in part by grants CA 107476, CA 168762,
and CA186781 from the National Cancer Institute, Rockville, MD,
USA.
CONFLICT OF INTERESTS
The author declares that there is no conflict of interest.
REFERENCES
1. Rajkumar SV, Dimopoulos MA, Palumbo A, et al. International
Myeloma Working Group updated criteria for the diagnosis of
multiple myeloma. Lancet Oncol. 2014;15:e538‐e548.
2. Rajkumar SV, Kumar S. Multiple myeloma current treatment
algorithms. Blood Cancer J. 2020;10:94.
3. Rajkumar SV. Multiple myeloma: 2020 update on diagnosis,
risk‐stratification and management. Am J Hematol. 2020;95:
548‐567.
4. Durie BGM, Hoering A, Abidi MH, et al. Bortezomib, lenalido-
mide and dexamethasone vs. Lenalidomide and dexamethasone
induction followed by lenalidomide and dexamethasone mainte-
nance in patients with newly diagnosed myeloma without intent
for immediate autologous stem cell transplant: results of the
randomised phase III SWOG trial S0777. Lancet. 2017;389:
519‐527.
5. Attal M, Lauwers‐Cances V, Hulin C, et al. Autologous trans-
plantation for multiple myeloma in the era of new drugs: a phase III
study of the Intergroupe Francophone du Myelome (IFM/DFCI 2009
trial). Blood. 2015;126:391.
6. Facon T, Kumar S, Plesner T, et al. Daratumumab plus lenalidomide
and dexamethasone for untreated myeloma. N Engl J Med. 2019;380:
2104‐2115.
7. Kapoor P, Rajkumar SV. MAIA under the microscope—
bringing trial design into focus. Nat Rev Clin Oncol. 2019;16:
339‐340.
8. Moreau P, Attal M, Hulin C, et al. Bortezomib, thalidomide, and
dexamethasone with or without daratumumab before and after
autologous stem‐cell transplantation for newly diagnosed multiple
myeloma (CASSIOPEIA): a randomised, open‐label, phase 3 study.
Lancet. 2019;394:29‐38.
9. Kumar SK, Jacobus SJ, Cohen AD, et al. Carfilzomib or bortezomib
in combination with lenalidomide and dexamethasone for newly
diagnosed myeloma without intent for immediate autologous
stem‐cell transplant (E1A11): a multicenter, open label, phase
3, randomised, controlled trial. Lancet Oncol. 2020;21(10):
1317‐1330.
RAJKUMAR
-
71
10. Attal M, Lauwers‐Cances V, Hulin C, et al. Lenalidomide, bortezomib,
and dexamethasone with transplantation for myeloma. N Engl J Med.
2017;376:1311‐1320.
11. Bringhen S, Mina R, Petrucci MT, et al. Once‐weekly versus twice‐
weekly carfilzomib in patients with newly diagnosed multiple
myeloma: a pooled analysis of two phase I/II studies. Haematologica.
2019;104:1640‐1647.
12. Lonial S, Lee HC, Badros A, et al. Belantamab mafodotin for relapsed
or refractory multiple myeloma (DREAMM‐2): a two‐arm,
randomised, open‐label, phase 2 study. Lancet Oncol. 2020;21:
207‐221.
13. Kumar S, Kaufman JL, Gasparetto C, et al. Efficacy of venetoclax as
targeted therapy for relapsed/refractory t(11;14) multiple myeloma.
Blood. 2017;130:2401‐2409.
14. Kumar S, Rajkumar SV. Surrogate endpoints in randomised
controlled trials: a reality check. Lancet. 2019;394:281‐283.
15. Raje N, Berdeja J, Lin Y, et al. Anti‐BCMA CAR T‐cell therapy
bb2121 in relapsed or refractory multiple myeloma. N Engl J Med.
2019;380:1726‐1737.
How to cite this article: Rajkumar SV. Sequencing of myeloma
therapy: Finding the right path among many standards.
Hematological Oncology. 2021;39(S1):68–72. https://doi.org/
10.1002/hon.2848
72
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RAJKUMAR
Received: 15 February 2021
DOI: 10.1002/hon.2849
SUPPLEMENT ARTICLE
Molecular diagnostics and reporting in lymphoid
malignancies: Current status and beyond
Richard Rosenquist
Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden
Correspondence
Richard Rosenquist, Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm 17176, Sweden.
Email: richard.rosenquist@ki.se
Funding information
The Swedish Cancer Society; The Swedish Research Council; The Knut and Alice Wallenberg Foundation; Radiumhemmets Forskningsfonder, Stockholm
1
|
INTRODUCTION
Thanks to the advent of next‐generation sequencing (NGS) technol-
ogies more than 10 years ago, the genomic landscape of most larger
cancer types has been unraveled. Hematological and lymphoid ma-
lignancies were among the first cancer types to be sequenced,
1
probably as they are more easily accessible. Based on these studies,
the number of clinically relevant genetic aberrations with diagnostic,
prognostic, and/or predictive impact has increased rapidly.
2
This
increases demands on molecular diagnostics to ensure that different
types of genetic alterations can be readily detected in a diagnostic
setting and within a reasonable time frame.
For hematological malignancies, genetics have been an integral
part of diagnostics since decades,
3
including methods such as cyto-
genetics, fluorescence in situ hybridization (FISH) and targeted
mutational analysis, and/or Sanger sequencing (Figure 1). With the
more powerful NGS technologies, targeted gene panels have been
added to the arsenal of methods in the diagnostic laboratory.
Regardless of the type of diagnostic test, it is essential to harmonize
methodology according to international standards and guidelines. To
ensure comparable results, especially in multicenter studies, it is
equally important that the interpretation of the results and the
clinical reporting follow established guidelines. This is particularly
relevant as genetic test results are becoming more complex with
different NGS assays covering a range of different genetic
aberrations.
This paper gives an overview of different state‐of‐the‐art molec-
ular technologies that are applied in clinical diagnostics of lymphoid
malignancies, their advantages, and limitations. It also discusses
aspects that need to be considered to harmonize clinical interpre-
tation and reporting of NGS data.
2
|
TECHNOLOGIES APPLIED FOR DIAGNOSTICS
OF LYMPHOID MALIGNANCIES
2.1
|
Molecular cytogenetics
Cytogenetics, or chromosome banding analysis, has long been
instrumental to define recurrent chromosomal aberrations observed
in different lymphoid malignancies. While cytogenetics has remained
central in leukemias (i.e., acute myeloid leukemia [AML], acute
lymphoblastic leukemia [ALL], and chronic myeloid leukemia),
molecular cytogenetics or FISH is preferred for mature lymphoid
malignancies. The introduction of the FISH technology enabled
analysis not only on metaphase chromosomes, but also on interphase
chromosomes (i.e., nondividing cells). FISH is therefore more rapid
than cytogenetics and can be used to screen for recurrent diagnostic
or risk stratifying genomic aberrations. Moreover, FISH can be
applied to various tissue types, such as blood smears, imprints as well
as formalin‐fixed, paraffin‐embedded (FFPE) tissue. Robust, com-
mercial FISH probes are available for most recurrent aberrations,
although they are relatively expensive. It is commonly used to detect
translocations in lymphomas; for example, t(11;14) in mantle cell
lymphoma and MYC and BCL2 translocations in diffuse large B‐cell
lymphoma (DLBCL).
3
In chronic lymphocytic leukemia (CLL), a panel
of probes is usually applied to detect risk‐stratifying aberrations, that
is, 11q‐deletion, 13q‐deletion, 17p‐deletion, and trisomy 12, whereas
This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, pro-
vided the original work is properly cited.
© 2021 The Authors. Hematological Oncology published by John Wiley & Sons Ltd.
Hematological Oncology. 2021;39(S1):73–77. wileyonlinelibrary.com/journal/hon
-
73
in multiple myeloma, probes are used to identify t(4;14), t(11;14),
t(14;16), 1q gain, and 17p deletion. However, while FISH on inter-
phase cells can give a quick answer as to whether a specific genetic
aberration is present or not, it is not a particularly sensitive
technique; the cutoff level to detect an aberration has to be deter-
mined by each laboratory and is usually around 5%.
2.2
|
Targeted mutation analysis
Before the NGS era, most clinical laboratories applied Sanger
sequencing for targeted mutation analysis. Sanger sequencing has
been the gold standard since the 1980s and is a very robust
technology. However, it rapidly becomes expensive and time
consuming if several genes or large genes are investigated. Another
limitation with Sanger sequencing is its sensitivity which is usually
between 10% and 20%.
In CLL, TP53 mutations are linked to poor response to chemo-
immunotherapy and poor overall survival, and TP53 gene screening is
nowadays mandatory before start of any line of treatment.
4
TP53
gene analysis (encompassing exons 2‐11) has typically been
performed by Sanger sequencing, although more recently many
laboratories have shifted to NGS.
Another sequenced‐based molecular test is the immunoglobulin
heavy variable (IGHV) gene mutational status that defines CLL with
unmutated IGHV genes and an inferior outcome, and CLL with
mutated IGHV genes and an expected favorable prognosis. This
analysis is mainly performed by polymerase chain reaction (PCR)
amplification of the clonal IGH rearrangement followed by Sanger
sequencing,
5
although new NGS protocols have been developed.
6
For both TP53 analysis and IGHV gene analysis, the European
Research Initiative on CLL (ERIC) has provided technical recom-
mendations and guidance for interpretation.
4,5
It has also imple-
mented dedicated certification systems that enable clinical
laboratories to regularly certify their method (Sanger sequencing or
NGS) against standard operation procedures.
For hotspot mutation detection, such as BRAF (V600E) in hairy
cell leukemia and MYD88 mutations (L265P) in Waldenström's
macroglobulinemia, specific assays have been established. These use
allele‐specific PCR or quantitative PCR to detect the mutant allele.
More recently, digital droplet PCR has been developed that enables a
very sensitive detection (down to 0.01%) and can be applied to detect
recurrent mutations or to follow patients over time. It is, for instance,
used to detect BTK/PLCG2 mutations in CLL patients progressing on
ibrutinib treatment.
2.3
|
Next‐generation sequencing
Since more than 10 years, we have had access to new types of
sequencing instruments that provide massive parallel sequencing or
NGS. Using this technology, we can analyze the entire genome
(whole‐genome sequencing [WGS]), the exome (whole‐exome
sequencing), or selected regions of particular interest, that is,
targeted NGS or gene panels. Depending on the detail of sequencing,
the number of obtained sequence reads differs. Using WGS, the
recommendation for tumor samples is to sequence to a sequence
depth of 90�(and 30�for the matched normal sample). For targeted
gene panels, depending on the size of the panel, one aims for a high
sequence depth of at least 500�but preferably above 1000�.
Until recently, the majority of gene panels used within clinical
diagnostics were amplicon‐based, meaning they use PCR to amplify
selected amplicons covering the genes/exons of interest. These
amplicon‐based panels can be implemented relatively easily using
either a panel that is designed in‐house, or commercially available
panels. However, the limitations with amplicon‐based technology are
potential biases in amplification, particularly in difficult to sequence
regions (i.e., GC rich and/or repetitive regions), that can cause
drop‐out of amplicons, as well as an increased risk of low‐frequency,
false‐positive mutations; this can happen in particular when FFPE
material is used as source of input.
In an attempt to study the robustness of amplicon‐based gene
panels, we within ERIC recently conducted a multicenter study using
three different technologies (Multiplicom, HaloPlex, and TruSeq),
targeting 11 genes recurrently mutated in CLL.
7
All six centers
analyzed the same 48 CLL samples, and each technique was analyzed
FIGURE 1 Evolution of genetic diagnostics. FISH, fluorescence in situ hybridization
74
-
ROSENQUIST
by two centers. A very high concordance was achieved between
technologies and centers for gene mutations with a variant allele
frequency (VAF) above 5%, while discrepancies started to appear for
variants with a VAF <5%. Hence, we conclude that amplicon‐based
sequencing can be safely adopted for somatic mutation detection
with VAFs >5%.
We also tested a high‐sensitivity assay containing unique
molecular identifiers (UMIs) which could confirm subclonal mutations
with a VAF <5%.
7
In this approach, duplicate reads are removed
which improved sensitivity. Therefore, inclusion of UMIs should be
considered when new panels are designed.
More recently, capture‐based enrichment panels, using baits
(probes) to hybridize to the region of interest, have been developed.
These panels are usually larger in size (hundreds of genes) and
produce more even sequence reads. This means that more “prob-
lematic” regions can be sequenced. Another advantage is that they
enable simultaneous detection of different types of genomic
aberrations (as they are larger in size). For instance, in addition to
investigating a selected number of genes for single nucleotide
variants (SNVs) and insertions/deletions (indels), it is also possible to
analyze copy‐number changes (i.e., deletions and amplifications) and
structural variants (e.g., translocations). He et al.
8
combined a DNA
and RNA‐based broad, capture‐based gene panel for diagnostics of a
large number of hematological malignances (n=3696) including
different lymphoid malignancies. Using either bone marrow or FFPE
samples, they could detect all aforementioned types of genomic
aberrations with high accuracy and reproducibility.
Gene panels have rapidly been introduced into routine
diagnostics of myeloid malignancies. In Sweden, we recently shifted
from a 54 gene amplicon‐based gene panel to a national capture‐
based myeloid panel including 195 genes. In lymphoid malignancies,
smaller amplicon‐based gene panels are currently in clinical use. As
mentioned, in CLL, we test for TP53 mutations before start of
treatment and many centers have switched to amplicon‐based
NGS‐gene panels. There are also additional genes of diagnostic,
prognostic, and predictive impact in lymphomas that can be captured
with these smaller panels. For instance, detection of certain muta-
tions has diagnostic utility, for example, MYD88 mutations in
Waldenström's macroglobulinemia, BRAF mutations in hairy cell
leukemia, KLF2 mutations in splenic marginal zone lymphomas, and
STAT3/STAT5B mutations in T‐cell lymphomas, while other gene
mutations are associated with response to treatment (e.g., MYD88/
CXCR4 mutations in Waldenström's macroglobulinemia patients
treated with ibrutinib) or treatment resistance (e.g., BTK/PLCG2
mutations in ibrutinib‐treated CLL).
2
Considering that a broad spectrum of genetic aberrations is
involved in ontology and evolution of lymphoid malignancies,
1
the
introduction of capture‐based panels will be particularly useful in this
patient group to capture not only SNV/indels, but also copy‐number
aberrations (CNAs) and translocations
9
as well as more complex
markers such as IG/T‐cell receptor gene analysis. In Sweden, we have
recently developed a (national) capture‐based lymphoid panel
including 252 genes that is currently under validation and will soon
be implemented into routine diagnostics.
3
|
REPORTING AND INTERPRETATION OF
RESULTS
For all types of molecular reports, it is important to include a number
of key parameters so that the results can be easily understood by
other laboratories. The report should include general information,
such as personal id, referring doctor, and more specific information,
such as tissue type investigated, method applied, and genetic aber-
rations assessed (Table 1). For FISH analysis, it is important to state
the probes used and number of cells investigated as well as the cutoff
applied. For more targeted analyses, such as hotspot mutation
detection, the technology, and sensitivity should also be provided.
For NGS‐based analysis, it is important to state gene coverage
and sequence depth as well as cutoffs for variant calling. The
sequence variants should be listed and include variant description at
cDNA/protein level, following the HGVS nomenclature, the number
of variant reads versus total number of sequence reads and the VAF
(Table 1). It should also be noted if the variant has been deemed as
pathogenic using locus‐specific databases or international guidelines
(e.g., following the American College of Medical Genetics (ACMG)
criteria
10
). Furthermore, in the concluding remark of the report, it
should be stated if a somatic variant has been detected before in this
disease entity that has diagnostic, prognostic, or predictive impact,
based on the WHO classification,
3
clinical consensus guidelines, or
available published literature. More complex data that includes CNAs
and/or structural aberrations will require continued development of
bioinformatics tools to visualize the reported data, for example, in
the format of copy‐number plots or circus plots.
As we enter the precision medicine era, more and more targeted
therapies have become available in oncology. Some academic centers
and commercial companies have developed new support systems for
clinical decision‐making that assist in defining if a mutation is
considered “actionable” or not.
11
Based on large databases, these
tools can, for a certain variant, provide an alert if a clinically relevant
finding has been made and provide links to available potential
targeted drugs and/or clinical trials (e.g., FDA‐approved drugs,
ongoing clinical trials, or if a drug has been used for another malig-
nancy). Thus far, these support systems have been mainly used for
solid cancer and less frequently in hematological malignancies.
4
|
CONCLUDING REMARKS
Genetic diagnostics within hematological malignancies has over the
years evolved dramatically from cytogenetics to targeted NGS
strategies (Figure 1). For lymphoid malignancies, we apply different
FISH analysis as well as targeted sequencing/NGS for diagnostic and
risk‐stratifying purposes.
3
However, with the ever‐increasing
ROSENQUIST
-
75
TABLE 1Data to be included in the molecular report based on sequencing
Basic data: Patient data (name, date of birth and/or id number)
Diagnosis
Type of material (peripheral blood, bone marrow, lymph node)
Date of sample collection/delivery
Requested by (department/hospital)
Method: Sequencing strategy: Sanger sequencing, amplicon‐based NGS or capture‐based NGS
Genes/exons analyzed, minimum/mean sequence depth, detection limit, reference
sequence
Results: Variant description (cDNA/protein level)
Variant type (missense/non‐sense/frameshift)
Variant allele frequency (number of variant reads/total number of reads)
Variant pathogenicity
Conclusion: Clinical interpretation of the variant detected and summary of its clinical impact
(diagnostic, prognostic and/or predictive) according to current knowledge
Abbreviation: NGS, next‐generation sequencing.
number of clinically relevant genetic variants that are detected in
lymphoid malignancies, we need to continue developing “dynamic”
NGS‐based strategies, such a capture‐based sequencing, that include
large numbers of genes and types of genetic aberrations. In this
regard, a recent study identified seven novel distinct subgroups of
DLBCL based on broad genetic characterization.
12
This illustrates
the need to develop more comprehensive analyses for diagnostic
purposes, also to carry out future precision medicine studies.
Furthermore, it is important to develop decision support tools that
can inform clinicians on “actionability” for the different genetic
events detected.
Within rare disease diagnostics, WGS has increasingly replaced
multigene testing.
13
Could this be a way forward also for hemato-
logical malignancies where we usually perform multiple testing? Some
national and/or regional programs are now testing if WGS combined
with RNA‐sequencing could replace the “old” technologies in acute
leukemia (ALL and AML). In a proof‐of‐concept study, Klintman et al.
demonstrated that WGS and targeted NGS had a high concordance
for SNVs/indels in CLL, while the concordance between FISH and
WGS was lower.
14
Hence, before we can start to use whole‐genome
techniques, we have to be certain that all mandatory genomic aber-
rations can be detected and provided within a reasonable time frame.
Another rapidly evolving areas of interest are liquid biopsies and
the detection of circulating tumor DNA, which have the potential to
enable sensitive NGS‐based follow‐up of lymphoma patients and can
detect genetic aberrations in cases where it is difficult to take a
biopsy.
15
These analyses have not yet entered clinical use in
lymphoid malignancies, but they are foreseen to be an important part
of future diagnostics.
Finally, although there are a few ongoing precision medicine
studies in lymphoid malignancies world‐wide, it will be very impor-
tant to initiate future clinical trials based on targeted drugs/immune
therapy to realize the full potential of precision medicine.
CONFLICT OF INTEREST
Richard Rosenquist has received honoraria from Abbvie, AstraZe-
neca, Illumina, Janssen and Roche.
PEER REVIEW
The peer review history for this article is available at https://publons.
com/publon/10.1002/hon.2849
ORCID
Richard Rosenquist https://orcid.org/0000-0002-0211-8788
REFERENCES
1. Rosenquist R, Bea S, Du MQ, Nadel B, Pan‐Hammarstrom Q. Genetic
landscape and deregulated pathways in B‐cell lymphoid malig-
nancies. J Intern Med. 2017;282(5):371‐394.
2. Rosenquist R, Rosenwald A, Du MQ, et al. Clinical impact of recur-
rently mutated genes on lymphoma diagnostics: state‐of‐the‐art and
beyond. Haematologica. 2016;101(9):1002‐1009.
3. Swerdlow SHCE, Harris NL, Jaffe ES, Pileri SA, Stein H, Thiele J.
WHO Classification of Tumours of Haematopoietic and Lymphoid
Tissues. Rev. 4th ed. 2017:586.
4. Malcikova J, Tausch E, Rossi D, et al. ERIC recommendations for
TP53 mutation analysis in chronic lymphocytic leukemia‐update on
methodological approaches and results interpretation. Leukemia.
2018;32(5):1070‐1080.
5. Rosenquist R, Ghia P, Hadzidimitriou A, et al. Immunoglobulin gene
sequence analysis in chronic lymphocytic leukemia: updated ERIC
recommendations. Leukemia. 2017;31(7):1477‐1481.
6. Davi F, Langerak AW, de Septenville AL, et al. Immunoglobulin gene
analysis in chronic lymphocytic leukemia in the era of next genera-
tion sequencing. Leukemia. 2020;34(10):2545‐2551.
7. Sutton LA, Ljungstrom V, Enjuanes A, et al. Comparative analysis of
targeted next‐generation sequencing panels for the detection of
gene mutations in chronic lymphocytic leukemia: an ERIC multi‐
center study. Haematologica. 2020.
8. He J, Abdel‐Wahab O, Nahas MK, et al. Integrated genomic DNA/
RNA profiling of hematologic malignancies in the clinical setting.
Blood. 2016;127(24):3004‐3014.
76
-
ROSENQUIST
9. Wren D, Walker BA, Bruggemann M, et al. Comprehensive trans-
location and clonality detection in lymphoproliferative disorders by
next‐generation sequencing. Haematologica. 2017;102(2):e57‐e60.
10. Richards S, Aziz N, Bale S, et al. Standards and guidelines for the
interpretation of sequence variants: a joint consensus recommen-
dation of the American College of Medical Genetics and Genomics
and the Association for Molecular Pathology. Genet Med. 2015;17(5):
405‐424.
11. Tamborero D, Dienstmann R, Rachid MH, et al. Support systems to
guide clinical decision‐making in precision oncology: the Cancer
Core Europe Molecular Tumor Board Portal. Nat Med. 2020;26(7):
992‐994.
12. Wright GW, Huang DW, Phelan JD, et al. A probabilistic classifica-
tion tool for genetic subtypes of diffuse large B cell lymphoma with
therapeutic implications. Cancer Cell. 2020;37(4):551‐568.
13. Lindstrand A, Eisfeldt J, Pettersson M, et al. From cytogenetics to
cytogenomics: whole‐genome sequencing as a first‐line test
comprehensively captures the diverse spectrum of disease‐causing
genetic variation underlying intellectual disability. Genome Med
2019;11(1):68.
14. Klintman J, Barmpouti K, Knight SJL, et al. Clinical‐grade validation
of whole genome sequencing reveals robust detection of low‐
frequency variants and copy number alterations in CLL. Br J
Haematol. 2018;182(3):412‐417.
15. Rossi D, Diop F, Spaccarotella E, et al. Diffuse large B‐cell lymphoma
genotyping on the liquid biopsy. Blood. 2017;129(14):1947‐1957.
How to cite this article: Rosenquist R. Molecular diagnostics
and reporting in lymphoid malignancies: Current status and
beyond. Hematological Oncology. 2021;39(S1):73–77. https://
doi.org/10.1002/hon.2849
ROSENQUIST
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DOI: 10.1002/hon.2859
SUPPLEMENT ARTICLE
New drugs and pharmacological interactions in real life
Anastasios Stathis
New Drugs Development Unit, Oncology
Institute of Southern Switzerland, Bellinzona,
Switzerland
Correspondence
Anastasios Stathis, Head‐New Drugs
Development Unit, Oncology Institute of
Southern Switzerland, 6500 Bellinzona,
Switzerland.
Email: anastasios.stathis@eoc.ch
Abstract
A high number of new drugs have entered clinical development and many of them
have recently been approved for patients with lymphoid malignancies. The avail-
ability of new drugs offers additional treatment options, but it also requires
particular attention for the emergence of adverse events. In addition, new drugs
may also have interactions with other drugs, which could further increase the risk of
toxicities or result in decreased efficacy. Here we review potential drug interactions
for nonchemotherapy new drugs approved for patients with lymphoid malignancies.
KEYWORDS
drug interactions, lymphoid malignancies, new drugs
1
|
INTRODUCTION
Over the last years, several new drugs including small molecules,
monoclonal antibodies (either naked or conjugated), and more
recently adoptive cell therapies have been approved for the treat-
ment of patients with lymphoid malignancies.
1–8
With the exception
of chimeric antigen receptor‐T cells, most of the new drugs are
administered chronically (i.e., up to disease progression or relapse or
up to the occurrence of adverse events) aiming to achieve long‐term
disease control. However, long‐term drug administration can result in
adverse events and may also increase the risk of interactions with
other drugs.
While recognized as a potential risk, the frequency and severity
of drug–drug interactions (DDIs) in oncology is not clear. Here, we
review current knowledge regarding potential interactions that may
involve drugs that have become recently available for patients with
lymphoid malignancies and may affect every day clinical practice.
2
|
DDIs IN ONCOLOGY
Interactions among concomitantly administered drugs can result in
changes in the way one drug acts in the body and thus to altered
efficacy or toxicity. DDIs can derive from pharmacokinetic, pharma-
codynamic, or pharmaceutical interactions among two drugs (or
among a drug and alternative medications, herbs, or food).
9
A
pharmacokinetic interaction may affect any of the pharmacokinetic
properties (absorption, distribution, metabolism, and/or excretion
[ADME]) of one drug by another. The best‐characterized is based on
cytochrome P450 (CYP) hepatic enzymes and occurs when drugs that
reduce (CYP inhibitors) or increase (CYP inducers) CYP activity are
concomitantly administered with CYP substrates resulting respec-
tively in decreases or increases in the metabolism of the substrate
drug. Interestingly, not only drugs but also food or herbs can have an
effect on CYP and therefore interfere with the metabolism of CYP
substrates, like grapefruit juice and Seville oranges that can act
respectively as strong or moderate CYP3A inhibitors and St. John's
wort that can induce CYP3A. Other pharmacokinetic interactions can
also occur, including interactions with the P glycoprotein 1 (P‐gp)
drug transporter that can result in altered drug exposure and finally
altered pharmacokinetic properties.
10
Pharmacodynamic and pharmaceutical interactions occur,
respectively, when two drugs have similar mechanism of action (and
therefore can result in additive, synergistic, or antagonistic effects) or
when there are physical or chemical incompatibilities.
9
Drug interactions represent an important issue in oncology
given the older age of patients with cancer and the frequent use of
several medications (so‐called polypharmacy) used to treat cancer‐
related symptoms or concomitant diseases.
11
Older series including
mainly patients with solid tumors reported that up to one‐third of
cancer patients are exposed to potential DDIs.
12
Major potential
DDIs were identified in 16% of cancer patients in a large
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retrospective cohort
13
and up to 25% of patients on anticancer
treatments were found to have a potentially clinically significant
DDI in another study performed in one center.
14
A prospective trial
including also patients with hematological malignancies, reported
potential clinically relevant DDIs in 81 of 302 included patients
(27%).
15
Data from patients enrolled in phase II–IV clinical trials
with approved medications (mainly tyrosine kinases and monoclonal
antibodies) have been also published. DDIs that had to be avoided
or drugs to be used with caution were detected by protocol guid-
ance in 10% of patients, although the majority of subjects did not
have clinical relevant interactions based on pharmacist review. In
the same study, the use of the Lexicomp database detected mod-
erate to major DDIs in 24% of patients with 9.4% having a clinically
relevant DDI.
16
However, despite these data, the real frequency of DDIs in
oncology is unclear and there is lack of standardized criteria with
regards to clinical consequences and assessment of their severity.
17
For patients with lymphoid malignancies and especially those on
treatment with new drugs, data on DDIs are even scarcer. A recent
study performed in 118 patients with chronic lymphocytic leukemia
(CLL) on treatment with the Bruton's tyrosine kinase (BTK) inhibitor
ibrutinib showed that 64% of patients were on medications that
could increase ibrutinib toxicity and 3% on medications that could
decrease its efficacy.
18
Over the last years, improvements in our understanding of the
biology of lymphomas and advances in antibody technology have
permitted the development of many new compounds that have
become available for patients with lymphoma and CLL. These new
compounds comprise mainly small molecules and monoclonal anti-
bodies which have different mechanisms of action, different toxic-
ities, and potential for DDIs. Taking as a referral Food and Drug
Administration approvals of new drugs for lymphomas and CLL over
the last 5 years (Table 1), potential interactions, and recommenda-
tions for their management will be presented in the following
paragraphs.
3
|
BTK INHIBITORS
The development of BTK inhibitors has represented one of greatest
recent therapeutic achievements in the treatment of lymphoid
malignancies. Following the approval of ibrutinib, two other
compounds, acalabrutinib and zanubrutinib, have been recently
approved, while others are in clinical development and may be
added in the list of available therapies for the treatment of
lymphoid malignancies responding to BTK inhibitors currently
including CLL, mantle‐cell lymphoma, marginal lymphoma, and
Waldenström's macroglobulinemia.
BTK inhibitors represent a class of compounds with known
potential of pharmacokinetic DDIs. The first‐in‐class inhibitor ibru-
tinib is primarily metabolized by the cytochrome P450 CYP3A.
19
Although clinical trials in patients with CLL and lymphoma have
excluded concomitant use of strong CYP3A inhibitors or inducers,
pharmacokinetic studies in healthy volunteers and physiologically
based pharmacokinetic models have revealed changes in ibrutinib
exposure when administered concomitantly with CYP3A inhibitors or
inducers that may be clinically relevant.
20,21
Accordingly, it is rec-
ommended to avoid concomitant administration of ibrutinib with
strong CYP3A inhibitors or inducers and to consider a reduction of
its dose if a moderate CYP3A inhibitor must be used.
22
In addition to
the abovementioned CYP3A‐mediated interactions which may have a
clinical consequence, there is in vitro evidence that ibrutinib may also
interact with rituximab antagonizing its antibody‐dependent cell‐
mediated cytotoxicity though inhibition of interleukin‐2 inducible
tyrosine kinase which is necessary for natural killer cell function.
23
However, the clinical significance of this possible interaction is not
known.
Similarly to ibrutinib, the second generation BTK inhibitors
acalabrutinib and zunabrutinb are also primarily metabolized by
CYP3A, and they have the same recommendation of avoiding coad-
ministration with strong CYP3A inhibitors or inducers. Adaptations
of their dose should be considered when CYP3A moderate inducers
or inhibitors must be used.
24,25
In addition, acalabrutinib solubility
decreases with increasing gastric pH resulting in significant decreases
in exposer when administered with antacids and proton‐pump in-
hibitors. Therefore, the recommendation is that acalabrutinb should
not be coadministered with proton‐pump inhibitors (due to their
long‐lasting effect), while antacids and H2‐receptor antagonists may
be administered but at least 2 h after the administration of
acalabrutinib.
While the above reported interactions are based on pharmaco-
kinetic mechanism and modulation of CYP3A, there are other
potential interactions of BTK inhibitors that should be taken in
consideration. In particular, attention should be given to the
concomitant administration of anticoagulants which can lead to
increased risk of bleeding events. Concomitant administration of
warfarin is contraindicated. On the other hand, apixaban and rivar-
oxaban undergo CYP3A4‐mediated metabolism.
26,27
4
|
PHOSPHOINOSITIDE 3‐KINASE INHIBITORS
Another class of compounds that have entered clinical development
and have beshown activity mainly in CLL and some indolent lym-
phomas (follicular lymphoma in particular) is represented by phos-
phoinositide 3‐kinase (PI3K) inhibitors. Following the first approval
of idelalisib, other compounds targeting PI3K have been developed
more recently and two of them, copanlisib and duvelisib, have been
approved for follicular lymphoma.
Copanlisib is an intravenous, pan‐class I phosphatidylinositol‐3‐
kinase (PI3K inhibitor) with predominant PI3K‐α and PI3K‐δ inhibi-
tory activity. Approximately more than 90% of copanlisib metabolism
is mediated by CYP3A. Strong CYP3A inducers result in significant
decreases of copanlisib AUC and Cmax and should not be given
concomitantly. On the other hand, CYP3A strong inhibitors cause a
significant increase of copanlisib AUC and again should not be
STATHIS
-
79
administered concomitantly, or the dose of copanlisib should be
reduced in case concomitant use with strong inhibitors cannot be
avoided.
28
Finally, duvelisib, an inhibitor of PI3K with inhibitory activity
predominantly against PI3K‐δ and PI3K‐γ isoforms, is also primary
metabolized by CYP3A cytochrome and has the same indications as
with copanlisib for strong inducers or inhibitors. In addition, duvelisib
can lead to increase AUC of CYP3A substrates and therefore to
increased toxicity of these drugs which may require adaptation of
their dose.
29
5
|
VENETOCLAX
Another small molecule‐targeted agent that has been approved for
the treatment of CLL is the bcl‐2 inhibitor venetcolax. As with the
compounds previously reported, venetoclax is mainly metabolized by
the cytochrome CYP3A4.
30
Concomitant use with a strong or mod-
erate CYP3A inhibitor or a P‐gp inhibitor increases venetoclax
plasma concentration and exposure which may increase the risk of
adverse events, including tumor lysis syndrome, a well‐known
adverse event of venetoclax in CLL and reason for a particular
TABLE 1Selected recently approved drugs for lymphoid malignancies with known CYP3A and/or P‐gp interactions. Refer to the
prescribing information of each drug.
Drug Recommendation Effects on other drugs
Ibrutinib Avoid concomitant use with strong CYP3A inhibitors. If these
inhibitors are used as short‐term consider interrupting
ibrutinib
May increase the concentration of oral P‐gp or BCRP substrates
with narrow therapeutic index (e.g. digoxin, methotrexte).
Dose adjustments (70 mg OD or 140 mg OD) if voriconazole or
posaconazole must be given concomitantly
Dose adjustment to 280 mg OD if a moderate inhibitor must be
administered concomitantly
Strong CYP3A inducers should be avoided
Acalabrutinib Coadministration with strong CYP3A inhibitors should be avoided
or, if the inhibitor will be used short‐term, acalabrutinib should
be interrupted
Not reported
Dose adjustment at 100 mg OD if moderate CYP3A inhibitors are
used
Coadministration with strong CYP3A inducers should be avoided.
If they must be used consider increasing the dose of
acalabrutinib at 200 mg BID
Proton‐pump inhibitors should be avoided
Antacids and H2‐receptor antagonists to be taken at least 2 h after
acalabrutnib
Zanubrutinib Zanubrutinib dose to be reduced in case of concomitant
administration with moderate or strong CYP3A inhibitors
Not reported
Avoid coadministration with moderate or strong CYP3A inducers
Copanlisib Concomitant use with strong CYP3A inhibitors should be avoided.
Copanlisib dose to be reduced at 45 mg if a strong CYP3A
inhibitor must be used
Not reported
Strong CYP3A inducers should be avoided
Duvelisib Concomitant use with strong CYP3A inhibitors should be avoided.
Duvelisib dose to be reduced at 15 mg BID if a strong CYP3A
inhibitor must be used
May increase AUC of sensitive CYP3A4 substrates
Strong CYP3A inducers should be avoided
Venetoclax Strong CYP3A inhibitors should not be used during ramp‐up.
Venetoclax dose to be reduced when strong inhibitors are used
at steady state
May increase warfarin Cmax and AUCinf resulting in increased risk
of bleeding. Venetoclax increases Cmax and AUCinf of P‐gp
substrates
If moderate CYP3A or P‐gp inhibitors are used during ramp‐up or
at steady state, dose of venetoclax must be reduced
Concomitant use with strong or moderate CYP3A inducers should
be avoided
Abbreviations: CYP3A, cytochrome P450 3A; P‐gp, P glycoprotein 1.
80
-
STATHIS
ramp‐up dosing scheme. Therefore, the recommendation is to avoid
concomitant use with a strong CYP3A inhibitor at initiation and
during the ramp‐up phase. During treatment at the steady dose,
alternative medications or dose adaptation of venetoclax and
frequent monitoring for adverse events should be considered. Strong
or moderate CP3A inducers can also result in changes and in
particular in decreased exposure to venetoclax and therefore current
recommendation is to avoid concomitant administration.
Finally, venetoclax may also alter the exposure to other drugs
and in particular it can increase warfarin levels and thus increase
the risk of bleeding. International normalized ratio should there-
fore be regularly checked in patients taking warfarin with
venetoclax.
6
|
CONCLUSION
Drug interactions can involve recently approved new drugs for pa-
tients with lymphoid malignancies. In particular, small molecules‐
targeted agents are primary metabolized by CAP3A and their coad-
ministration with strong or moderate CYP3A inhibitors or inducers
can result respectively in increased or decreased plasma concentra-
tions and therefore in risks of toxicity or decreased efficacy.
Awareness of this problem and a regular check of the medications of
the patients and consultation with pharmacists in case of any doubts
for potential DDIs could help to prevent these interactions and
especially those that could result in clinically significant conse-
quences for patients.
CONFLICT OF INTERESTS
Institutional grants for clinical trials: Merck, Bayer, Roche, Novartis,
Pfizer, ADC Therapeutics, MEW Pharma, Eli Lilly; advisory board:
Roche; consultant: Bayer, Eli Lilly; travel grant: PharmaMar, Abbvie.
DATA AVAILABILITY STATEMENT
Data sharing not applicable to this article as no datasets were
generated or analyzed during the current study.
REFERENCES
1. Byrd JC, Furman RR, Coutre SE, et al. Targeting BTK with ibrutinib
in relapsed chronic lymphocytic leukemia. N Engl J Med.
2013;369:32‐42.
2. Wang ML, Rule S, Martin P, et al. Targeting BTK with ibrutinib in
relapsed or refractory mantle‐cell lymphoma. N Engl J Med.
2013;369:507‐516.
3. Byrd JC, Harrington B, O'Brien S, et al. Acalabrutinib (ACP‐196) in
relapsed chronic lymphocytic leukemia. N Engl J Med. 2016;374:323‐
332.
4. Roberts AW, Davids MS, Pagel JM, et al. Targeting BCL2 with
venetoclax in relapsed chronic lymphocytic leukemia. N Engl J Med.
2016;374:311‐322.
5. Dreyling M, Morschhauser F, Bouabdallah K, et al. Phase II study of
copanlisib, a PI3K inhibitor, in relapsed or refractory, indolent or
aggressive lymphoma. Ann Oncol. 2017;28:2169‐2178.
6. Sehn LH, Herrera AF, Flowers CR, et al. Polatuzumab vedotin in
relapsed or refractory diffuse large B‐cell lymphoma. J Clin Oncol.
2020;38:155‐165.
7. Neelapu SS, Locke FL, Bartlett NL, et al. Axicabtagene ciloleucel CAR
T‐cell therapy in refractory large B‐cell lymphoma. N Engl J Med.
2017;377:2531‐2544.
8. Schuster SJ, Bishop MR, Tam CS, et al. Tisagenlecleucel in adult
relapsed or refractory diffuse large B‐cell lymphoma. N Engl J Med.
2019;380:45‐56.
9. Beijnen JH, Schellens JH. Drug interactions in oncology. Lancet
Oncol. 2004;5:489‐496.
10. König J, Müller F, Fromm MF. Transporters and drug‐drug in-
teractions: important determinants of drug disposition and effects.
Pharmacol Rev. 2013;65:944‐966.
11. Scripture CD, Figg WD. Drug interactions in cancer therapy. Nat Rev
Cancer. 2006;6:546‐558.
12. Riechelmann RP, Del Giglio A. Drug interactions in oncology: how
common are they? Ann Oncol. 2009;20:1907‐1912.
13. van Leeuwen RWF, Brundel DHS, Neef C, et al. Prevalence of po-
tential drug‐drug interactions in cancer patients treated with oral
anticancer drugs. Br J Cancer. 2013;108:1071‐1078.
14. Mouzon A, Kerger J, D'Hondt L, Spinewine A. Potential interactions
with anticancer agents: a cross‐sectional study. Chemotherapy.
2013;59:85‐92.
15. van Leeuwen RWF, Jansman FGA, van den Bemt PMLA, et al. Drug‐
drug interactions in patients treated for cancer: a prospective study
on clinical interventions. Ann Oncol. 2015;26:992‐997.
16. Marcath LA, Coe TD, Hoylman EK, et al. Prevalence of drug‐drug
interactions in oncology patients enrolled on National Clinical Tri-
als Network oncology clinical trials. BMC Cancer. 2018;18:1155.
17. Bossaer JB, Eskens D, Gardner A. Sensitivity and specificity of drug
interaction databases to detect interactions with recently approved
oral antineoplastics. J Oncol Pharm Pract. 2021. https://doi.org/10.
1177/1078155220984244
18. Finnes HD, Chaffee KG, Call TG, et al. Pharmacovigilance during
ibrutinib therapy for chronic lymphocytic leukemia (CLL)/small
lymphocytic lymphoma (SLL) in routine clinical practice. Leukemia
Lymphoma. 2017;58:1376‐1383.
19. Scheers E, Leclercq L, de Jong J, et al. Absorption, metabolism, and
excretion of oral 14C radiolabeled ibrutinib: an open‐label, phase
I, single‐dose study in healthy men. Drug Metab Dispos.
2015;43:289‐297.
20. de Jong J, Skee D, Murphy J, et al. Effect of CYP3A perpetrators on
ibrutinib exposure in healthy participants. Pharmacol Res Perspect.
2015;3:e00156.
21. de Zwart L, Snoeys J, De Jong J, Sukbuntherng J, Mannaert E,
Monshouwer M. Ibrutinib dosing strategies based on interaction
potential of CYP3A4 perpetrators using physiologically based
pharmacokinetic modeling. Clin Pharmacol Ther. 2016;100:548‐557.
22. IMBRUVICA (Ibrutinib)—FDA. https://www.accessdata.fda.gov/
drugsatfda_docs/label/2015/205552s002lbl.pdf
23. Kohrt HE, Sagiv‐Barfi I, Rafiq S, et al. Ibrutinib antagonizes
rituximab‐dependent NK cell‐mediated cytotoxicity. Blood.
2014;123:1957‐1960.
24. Calquence—FDA. https://www.accessdata.fda.gov/drugsatfda_docs/
label/2017/210259s000lbl.pdf
25. Label—FDA. https://www.accessdata.fda.gov/drugsatfda_docs/label/
2019/213217s000lbl.pdf
26. Fancher KM, Pappacena JJ. Drug interactions with Bruton's tyrosine
kinase inhibitors: clinical implications and management. Cancer
Chemother Pharmacol. 2020;86:507‐515.
27. Stephens DM, Byrd JC. How I manage ibrutinib intolerance and
complications in patients with chronic lymphocytic leukemia. Blood.
2019;133:1298‐1307.
STATHIS
-
81
28. Aliqopa—FDA. https://www.accessdata.fda.gov/drugsatfda_docs/
label/2017/209936s000lbl.pdf
29. Duvelisib—FDA. https://www.accessdata.fda.gov/drugsatfda_docs/
label/2018/211155s000lbl.pdf
30. Venclexta—FDA. https://www.accessdata.fda.gov/drugsatfda_docs/
label/2019/208573s013lbl.pdf
How to cite this article: Stathis A. New drugs and
pharmacological interactions in real life. Hematological Oncology.
2021;39(S1):78–82. https://doi.org/10.1002/hon.2859
82
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STATHIS
Received: 26 February 2021
DOI: 10.1002/hon.2855
SUPPLEMENT ARTICLE
Vulnerabilities in the tumor and microenvironment in
follicular lymphoma
Ferran Araujo‐Ayala
1
|Patricia Pérez‐Galán
1,2
|Elias Campo
1,2,3,4
1
Department of Hematology‐Oncology,
Institut d'Investigacions Biomèdiques August
Pi I Sunyer (IDIBAPS), Barcelona, Spain
2
Hematological Neoplasms Program, Centro
de Investigación Biomédica en Red‐Oncología
(CIBERONC), Madrid, Spain
3
Hematopathology Unit, Pathology
Department, Hospital Clínic of Barcelona,
Barcelona, Spain
4
Department of Basic Clinical Practice,
University of Barcelona, Barcelona, Spain
Correspondence
Elias Campo, Hospital Clinic of Barcelona,
Calle Villarroel 170, 08036‐Barcelona, Spain.
Email: ecampo@clinic.cat
Abstract
Follicular lymphoma (FL) is a paradigm of tumors that require the interaction be-
tween tumor and microenvironment cells to foster their development from initial
steps to progression. Recent large‐scale genome studies have uncovered multiple
genetic alterations of FL that influence the microenvironment in two main di-
rections, promoting tumor cell survival and proliferation and facilitating their
evasion from immune antitumor signals. Understanding the crosstalk between tu-
mor B‐cells and the microenvironment will facilitate the identification of vulnera-
bilities that may offer novel targets for treatment of the patients. This review
highlights recent findings showing the effect of common genetic mutations modu-
lating the cell composition of the tumor microenvironment and the novel thera-
peutic perspectives to target these interactions.
KEYWORDS
follicular lymphoma, genomic alterations, microenvironment, target therapies
1
|
INTRODUCTION
Follicular lymphoma (FL) develops in the germinal center (GC) of
lymphoid follicles due, in most of the cases, to the acquisition of the t
(14;18) translocation in precursor cells of the bone marrow which
leads to the overexpression of the antiapoptotic protein BCL2. A
second early oncogenic event in FL is the introduction of somatic
mutations in the variable regions of immunoglobulin genes creating
novel N‐glycosylation sites for highly mannosylated glycans that
directly interact with endogenous lectins found in cells of the tumor
microenvironment (TME). These interactions activate B‐cell receptor
signals required for tumor development. The third pillar in early steps
of FL is recurrent mutations in epigenetic regulator genes that confer
selective growth advantages to the B‐cell and promote favorable
interactions with the microenvironment.
1,2
Further, development and
progression of FL are associated with subsequent acquisition of
additional genomic alterations that target different pathways related
to cell differentiation, survival, proliferation, dissemination, and
metabolic advantages among others. In addition to the genomic and
epigenomic alterations, FL cells modulate the microenvironment to
promote the tumor cell growth.
3
Understanding these complex
phenomena and the crosstalk between tumor and stromal cells may
facilitate the identification of vulnerabilities that will offer novel
targets for treatment of the patients.
2
|
FL GENOME AND NEW VULNERABILITIES
2.1
|
Epigenetic modulators
Large‐scale genomic studies combined with functional analysis have
elucidated the mutational profile of FL and defined the several
altered pathways involved in the pathogenesis of these tumors. The
most common aberrations are mutations in the epigenetic regulators
KMT2D (60%–90%), CREBBP/EP300 (50%–70%/10%–20%), and
EZH2 (10%–30%). The high frequency of these lesions, their findings
in “in situ” follicular neoplasia and acquisition in later steps in the
evolution indicate that they are very early events but also favor the
progression of the tumors.
4,5
The loss of function mutations in
the histone H3K4 methyltransferase KMT2D and in the H3K27
Hematological Oncology. 2021;39(S1):83–87. wileyonlinelibrary.com/journal/hon © 2021 John Wiley & Sons Ltd.
-
83
acetyltransferase CREBBP/EP300 together with the gain of function
in the H3K27 methyltransferase EZH2 tend to confer a repressive
functional state of the genes targeted by these chromatin modifiers
related to B‐cell differentiation and cell cycle regulation that main-
tain tumor cells in a GC stage (Table 1).
1,5
Particularly, CREBBP mu-
tations silence genes that are direct targets of the BCL6‐HDAC3
onco‐repressor complex, including those that regulate B‐cell
signaling and immune responses, such as class II major histocom-
patibility complex (class II MHC). Other B‐cell neoplasias, such as
Hodgkin's lymphoma and primary mediastinal large B‐cell lymphoma
show class II MHC deregulation, but the mechanism is different
mainly associated with CIITA alterations.
6
CREBBP‐mutated tumors
also seem to have less helper and cytotoxic T‐cells in the microen-
vironment suggesting that these mutations favor tumor cell immune
evasion.
5,6
These crucial alterations in FL pathogenesis support the
idea that CREBBP may be a gene with high therapeutic potential. In
this sense, HDAC3 inhibition restores in part the immune responses
and therefore may represent a new therapeutic approach in FL.
7
Recent studies have also linked EZH2 mutations to the reprograming
of the tumor and microenvironment interactions. Mutant cells in the
light zone of the GC seem to be less dependent on T‐follicular helper
(T
FH
) cells while potentiate their interaction and dependence on
follicular dendritic cells (FDCs).
8
On the other hand, EZH2 also seems
to play a role in the development of T and natural killer (NK) cells.
The potential benefit of EZH2 inhibitors independently of its
mutational status may be related to this extra tumor cell activity.
Interestingly, Food and Drug Administration has approved the use of
the selective EZH2 inhibitor tazemetostat for adult relapse/re-
fractory (R/R) patients with EZH2‐mutated tumors and patients with
R/R FL who have no satisfactory alternative treatment options.
2.2
|
Immune evasion
Mutations and deletions of TNFRSF14 in 1p36, also known as
herpesvirus entry mediator A are a common event in FL (∼50%).
1
TNFRSF14 is the ligand for BTLA expressed in TFH cells and induces
inhibitory signals on these cells. The disruption of these interactions
results in increased recruitment of the tumor supportive T
FH
and
release of cytokines that also favor a pro‐TME. In addition,
TNFRSF14 generates inhibitory signals on the B‐cell receptor (BCR)
of the B‐cells that are released by the oncogenic inactivation. A
preclinical CAR‐T construct has been developed to continuously
produce soluble TNFRSF14 in the microenvironment that restores its
inhibitory function.
9
Ephrin receptor A7 (EPHA7) is a soluble tumor suppressor
inactivated in approximately 70% of FL by mutations and de-
letions. Loss of expression avoids its binding to EPHA2 receptor,
which inhibits extracellular regulated MAP kinase (ERK) and SRC
proto‐oncogene, non‐receptor tyrosine kinase oncogenic signals.
TABLE 1Genomic and microenvironment alterations in follicular lymphoma as potential targets for novel treatment
Target Type of alteration Biological consequence Targeted drug Combinations Status
Genomic aberrations
CREBBP Loss‐of‐function mutations Downregulation of MHC class II BRD3308 Anti‐PDL1 Preclinical
EZH2 Gain‐of‐function mutations Increased dependency on FDC Tazemetostat None Approved
TNFRSF14 Inactivating mutations Increased T
FH
recruitment CAR‐T None Preclinical
RRAGC Activating mutations Insensitivity to nutrient
deprivation
Temsirolimus Bendamustine rituximab Clinical
Increased B cell responses
FL‐microenvironment crosstalk
B‐cell receptor FL‐FDC BCR activation Ibrutinib Rituximab Clinical
FL‐DC‐SIGN
+
Mϕ
PI3KδFL‐T
FH
CD40‐CD40L activation, T
reg
recruitment
Idelalisib None Approved
FL‐T
reg
PI3Ky FL‐monocyte/MϕMyeloid cell recruitment, M2
polarization
Duvelisib None Approved
CSF‐1R FL‐MϕMyeloid cell recruitment and
differentiation, M2
polarization
Pexidartinib Rituximab Preclinical
CD47‐SIRP‐αFL‐MϕCD47
+
FL cells inhibit
phagocytosis by Mϕand
neutrophils
Anti‐CD47 Rituximab Clinical
FL‐neutrophils
Abbreviations: BCR, B‐cell receptor; FDC,follicular dendritic cell; FL, follicular lymphoma; MHC, major histocompatibility complex; T
reg
, T‐regulatory
cell; T
FH
, T‐follicular helper.
84
-
ARAUJO‐AYALA ET AL.
Therapies that restore EPHA7 function or inhibit downstream
oncogenic signals activated due to EPHA7 loss might be useful to
treat FL‐mutated patients.
10
Recent studies have identified mutations in mammalian target of
rapamycin complex 1 (mTORC1) pathway. Particularly, RRAGC acti-
vating mutations are present in 17% of FL patients. These mutations
activate mTORC1 bypassing amino acid deprivation and also confer
an independent requirement of T
FH
cells for tumor survival.
Concordantly, these tumors have less T
FH
cells in their stroma.
11
Thus, the identification of patients carrying mutations in this meta-
bolic pathway may benefit of selective inhibitors.
Cathepsin S (CTSS) has been found to be mutated (6%) or
overexpressed (13%) in FL leading to its hyperactivation.
12,13
CTSS
cleaves CD74, among other targets, which is fundamental for MHC II
assembly and antigen (Ag) presentation. Hyperactive CTSS yields a
more efficient Ag‐specific CD4+T activation, increased CD4+T‐cell
infiltration, and proinflammatory cytokine perturbation in FL mouse
models and human FL samples. Interestingly, the subversion of TME
by this alteration correlates with high PDL2 expression that yielded
FL patients more responsive to anti‐PD1 regimens, and also associ-
ates with better outcomes to immunochemotherapy (rituximab,
cyclophosphamide, doxorubicin, vincristine, and prednisone
[R‐CHOP]).
Other mutated genes in FL that also target the interactions be-
tween tumor cells and microenvironment are B2‐microglobulin and
CD58 that seem to be more common in transformed FL than in the
early steps of the disease.
1
Thus, reactivating their function may
improve cytotoxic response via CD8
+
T cells.
3
|
THERAPEUTIC OPPORTUNITIES FROM TME
Interaction of FL cells with nontumor cells constitutes a key feature
in the pathophysiology of the tumor. A precise characterization of the
TME could uncover new vulnerabilities to treat these patients. The
tumor niche of this lymphoma is composed of different cells types,
which create a tumor supportive environment and facilitate the scape
from the host antitumor immune responses. The main actors in this
TME are different subpopulations of T‐cells, myeloid derived cells,
mainly tumor‐associated macrophages (TAMs), and stroma cells,
mainly FDCs and cancer‐associated fibroblasts, among others. These
cells communicate among them and with tumor cells through a
network of cytokines and cell‐to‐cell interactions.
3.1
|
T‐cells
T‐cells are a heterogeneous group of cells that interplay with FL cells
at different levels mediating antitumor responses or, contrarily,
providing supportive protumoral signals. CD8
+
cytotoxic cells,
together with NK cells and probably Tγ/δcells, mediate antitumor
responses. However, FL cells may counteract this antitumor effect by
secreting interleukin 12 (IL‐12) that leads to an exhaustion of CD8
+
cells and by recruiting T‐regulatory cells (Tregs) that inhibit
degranulation and cytotoxic activity of CD8
+
cells.
14
On the other
side of the balance, two subpopulations of CD4
+
cell, T
FH
, and Treg
play key roles in providing tumor support and facilitating immune
evasion. In this way, T
FH
stimulate tumor B‐cells mediated by CD40L/
CD40 and MHC class II interactions.
15
These cells secrete IL‐4, which
triggers activation of B‐cells mediated by ERK and STAT6, and the
chemokine CCL22 that recruits immunomodulatory Treg cells. Treg
cells are a subset of CD4
+
cells characterized by the expression of
the transcription factor FOXP3. These cells seem to play a pro‐tumor
role due to their immunosuppressive activity on CD4 and CD8 cells.
However, a subset of T follicular regulatory cells (Tfr) has been also
recognized by the additional expression of BCL6, CXCR5, ICOS, and
PD1. These cells limit the expansion of the GC reaction and down-
regulate the effects of T
FH
cells. However, there is still some con-
troversy regarding the impact of Tfr FOXP3+expression patterns on
FL survival.
16,17
The relevance of T
FH
and Treg cells in FL has been highlighted by
the effect of PI3Kδinhibitors disrupting the crosstalk between FL
cells and T
FH
cells. In vitro studies have shown that the PI3Kδin-
hibitor idelalisib, diminishes tumor cell proliferation, and reshapes
immune microenvironment inhibiting the recruitment of classical
Treg cells by downregulating CCL22.
18
Finally, in this context of B–T‐cell crosstalk, FL cells present
immunoglobulin neoantigens that may play a determinant role in host
immune responses, and constitute potential immunotherapeutic
targets.
19
3.2
|
TAMs and other stromal cells
The role of TAMs in FL has been controversial. In the prerituximab
era, some studies suggested that macrophage infiltration correlated
with lower survival. Nevertheless, the addition of rituximab to che-
motherapeutical drugs modified their prognostic impact. The number
of infiltrating macrophages in patients treated with standard immu-
nochemoterapeutic regimens such as R‐CHOP was associated with
improved overall survival.
20
In addition to the influence of new therapies in the possible role
of TAM, different subpopulations of these cells may also play
different roles in the pathogenesis of FL. Macrophages polarized to a
M1 phenotype may exert antitumor properties by producing proin-
flammatory such as IL‐1, IL‐6, IL‐12, and tumor necrosis factor α,
whereas M2‐polarized macrophages are protumor since they are
able to downregulate MHC and IL‐12, as well as expressing anti‐
inflammatory molecules such as arginase and IL‐10, and the scav-
enger receptor CD163. Moreover, M2 macrophages are also involved
in tumor angiogenesis. The protumor effect of TAMs, particularly
with an M2 polarization, makes these cells and their interactions with
tumor cells an attractive target for therapies.
In is noteworthy, that contrary to other B‐cell lymphomas such
as diffuse large B‐cell lymphoma (DLBCL) or Hodgkin lymphoma, FL
cells do not express PD‐L1, and PD‐L2 is moderately expressed in a
ARAUJO‐AYALA ET AL.
-
85
high proportion of FL cases.
21
However, PD1 ligands are present in
the immune infiltrates where PD‐L1
+
histiocytes have been detected
in the T‐cell‐rich zone of the neoplastic follicles,
22
justifying the
therapeutic targeting of this pathway.
A target to interfere the FL‐TAMs crosstalk is the colony‐
stimulating factor 1 receptor (CSF‐1R), also known as macrophage
colony‐stimulating factor receptor, as it is a relevant element in the
differentiation and survival of macrophages. Noteworthy, high levels
of CSF‐1R expression in FL have been associated with higher histo-
logical grade and risk of transformation suggesting that targeting
CSF‐1R may be relevant in high‐risk patients. Although CSF‐1R is
expressed in both M1 and M2 subtypes, its inhibition by pexidartinib
preferentially diminish the viability of M2 macrophages and repo-
larize them to M1 macrophages suggesting that it may reeducated
TAMs toward an antitumor phenotype.
CD47 is a receptor usually expressed in cancer cells that pre-
vents phagocytosis forming a complex with signal‐regulatory protein
α(SIRP‐α). Among other phagocytes (e.g., neutrophils), macrophages
may express SIRP‐α in their membrane compromising their antitumor
phagocytic function when interacting with CD47‐positive lymphoma
cells (Table 1). By administrating a therapeutic antibody that blocks
CD47, phagocytosis of tumor cells is increased and adaptive immu-
nity is enhanced.
23
This effect has been explained by the Ag‐
presenting function of macrophages. After phagocytizing tumor
cells, macrophages may present tumor Ag to CD4
+
T‐helper cells
triggering an antitumor response. Altogether, anti‐CD47 antibodies
are now in clinical trials as promising drug candidates to activate the
immune system in FL, especially in combined immunotherapeutic
regimens including rituximab.
PI3Kγis expressed by microenvironment cells that support tu-
mor growth such as CD4 and M2 macrophages. The dual PI3Kγδ
inhibitor duvelisib exerts antitumor effects by targeting both the
tumor and microenvironment cells (Table 1). This compound inhibits
tumor cell proliferation and survival whereas also promotes the dif-
ferentiation of M2‐like TAMs to a M1 phenotype and inhibits the
antitumor effect of T‐cells interfering with the tumor supporting
properties of the TME. Other drugs that interfere with BCR pathway
such as ibrutinib may also affect the crosstalk of tumor cells and
macrophages. While BTK inhibitors (BTKi) have not showed optimal
results as monotherapy, the combination of the BTKi ibrutinib with
the anti‐CD20 rituximab has improved clinical trials results.
24
FDCs are from mesenchymal origin and build a network to
support the GC reaction. They are able to present antibody—Ag
complexes on their cell surface engaging BCR activation, survival
of malignant cells and recruitment of T
FH
cells.
18
Moreover, we
have recently demonstrated that FL‐FDC crosstalk induces mono-
cyte recruitment and their differentiation to M2‐protumoral
macrophages.
25
Other cell types that may play an important role in the disease
are different subsets of T‐cells, TAMs, mesenchymal stem cells, or
follicular reticular cells, among others. Interestingly, the evolution of
this TME might be determinant in the transformation of FL to DLBCL.
4
|
CONCLUDING REMARKS
Although in most cases FL initially presents as an indolent disease, a
significant proportion of cases are primary refractory to standard
treatment (R‐CHOP or derivatives) and a high percentage of those
who initially respond to treatment will eventually relapse. Once the
relapse occurs, the prognosis of the patients worsens, especially in
those who suffer an early relapse, within the first 24 months of
treatment progression of disease within 2 years. Furthermore, those
patients are in higher risk of histological transformation to an
aggressive lymphoma, mainly DLBCL. The evolution of the patients
cannot be precisely predicted exclusively based on single genetic
alterations. Recent studies have shown that assays that include
multiple genetic aberrations or combining both tumor B‐cell biology
and tumor microenvironment alterations may be better predictive
models. These findings reinforce the need to integrate the mutational
profile of the tumor cells together with the complex interactions of
the TME to predict the biological risk of the patients. This compre-
hensive perspective should assist in identifying tumor and microen-
vironment vulnerabilities that will allow treating them effectively and
avoiding early clinical progression.
ACKNOWLEDGMENTS
This study was funded by Ministerio de Ciencia e Innovación, Grant
No. RTI2018‐094274‐B‐I00 (to E. C.) and Fundacio la Marató TV3
(TAIFOL 201933‐30) (to P. P‐G.).
CONFLICT OF INTERESTS
The authors declare that there are no conflict of interests.
DATA AVAILABILITY STATEMENT
Data sharing not applicable to this article as no datasets were
generated or analyzed during the current study.
REFERENCES
1. Huet S, Sujobert P, Salles G. From genetics to the clinic: a trans-
lational perspective on follicular lymphoma. Nat Rev Cancer.
2018;18:224‐239.
2. Küppers R, Stevenson FK. Critical influences on the pathogenesis of
follicular lymphoma. Blood. 2018;131:2297‐2306. https://doi.org/10.
1182/blood‐2017‐11‐764365
3. Kridel R, Sehn LH, Gascoyne RD. Pathogenesis of follicular lym-
phoma. J Clin Invest. 2012;122:3424‐3431. https://doi.org/10.1172/
JCI63186
4. Schmidt J, Ramis‐Zaldivar JE, Bonzheim I, et al. CREBBP gene mu-
tations are frequently detected in in situ follicular neoplasia. Blood.
2018;132:2687‐2690.
5. Green MR. Chromatin modifying gene mutations in follicular lym-
phoma. Blood. 2018;131:595‐604. https://doi.org/10.1182/blood‐
2017‐08‐737361
6. Green MR, Kihira S, Liu CL, et al. Mutations in early follicular lym-
phoma progenitors are associated with suppressed antigen presen-
tation. Proc Natl Acad Sci USA. 2015;112:E1116‐E1125. https://doi.
org/10.1073/pnas.1501199112
7. Mondello P, Tadros S, Teater M, et al. Selective inhibition of HDAC3
targets synthetic vulnerabilities and activates immune surveillance
86
-
ARAUJO‐AYALA ET AL.
in lymphoma. Cancer Discov. 2020;10:440‐459. https://doi.org/10.
1158/2159‐8290.CD‐19‐0116
8. Béguelin W, Teater M, Meydan C, et al. Mutant EZH2 induces a pre‐
malignant lymphoma niche by reprogramming the immune response.
Cancer Cell. 2020;37:655‐673.e11. https://doi.org/10.1016/j.ccell.
2020.04.004
9. Boice M, Salloum D, Mourcin F, et al. Loss of the HVEM tumor
suppressor in lymphoma and restoration by modified CAR‐T cells.
Cell. 2016;167:405‐418.e13. https://doi.org/10.1016/j.cell.2016.
08.032
10. Oricchio E, Nanjangud G, Wolfe AL, et al. The Eph‐receptor A7
is a soluble tumor suppressor for follicular lymphoma. Cell.
2011;147:554‐564. https://doi.org/10.1016/j.cell.2011.09.035
11. Ortega‐Molina A, Deleyto‐Seldas N, Carreras J, et al. Oncogenic
Rag GTPase signalling enhances B cell activation and drives follic-
ular lymphoma sensitive to pharmacological inhibition of mTOR.
Nat Metab. 2019;1:775‐789. https://doi.org/10.1038/s42255‐019‐
0098‐8
12. Dheilly E, Battistello E, Katanayeva N, et al. Cathepsin S regulates
antigen processing and T cell activity in non‐Hodgkin lymphoma.
Cancer Cell. 2020;37:674‐689.e12. https://doi.org/10.1016/j.ccell.
2020.03.016
13. Bararia D, Hildebrand JA, Stolz S, et al. Cathepsin S alterations
induce a tumor‐promoting immune microenvironment in follicular
lymphoma. Cell Rep. 2020;31:107522. https://doi.org/10.1016/j.
celrep.2020.107522
14. Amé‐Thomas P, Tarte K. The yin and the yang of follicular lymphoma
cell niches: role of microenvironment heterogeneity and plasticity.
Semin Cancer Biol. 2014;24:23‐32. https://doi.org/10.1016/j.sem
cancer.2013.08.001
15. Amé‐Thomas P, Le Priol J, Yssel H, et al. Characterization of intra-
tumoral follicular helper T cells in follicular lymphoma: role in the
survival of malignant B cells. Leukemia. 2012;26:1053‐1063. https://
doi.org/10.1038/leu.2011.301
16. Carreras J, Lopez‐guillermo A, Fox BC, et al. High numbers of
tumor‐infiltrating FOXP3‐positive regulatory T cells are associated
with improved overall survival in follicular lymphoma. Blood.
2006;108:2957‐2964. https://doi.org/10.1182/blood‐2006‐04‐018
218.E.C
17. Farinha P, Al‐Tourah A, Gill K, Klasa R, Connors JM, Gascoyne RD.
The architectural pattern of FOXP3‐positive T cells in follicular
lymphoma is an independent predictor of survival and histologic
transformation. Blood. 2010;115:289‐295. https://doi.org/10.1182/
blood‐2009‐07‐235598
18. Serrat N, Guerrero‐Hernández M, Hernández H, et al. PI3Kd inhi-
bition reshapes follicular lymphoma‐immune microenvironment
cross talk and unleashes the activity of venetoclax. Blood Adv. 2020;
4(17):4217–4231. https://doi.org/10.1182/bloodadvances.202000
1584
19. Khodadoust MS, Olsson N, Chen B, et al. B‐cell lymphomas present
immunoglobulin neoantigens. Blood. 2019;133:878‐881.
20. Kridel R, Xerri L, Gelas‐Dore B, et al. The prognostic impact of
CD163‐positive macrophages in follicular lymphoma: a study from
the BC Cancer Agency and the Lymphoma Study Association. Clin
Cancer Res. 2015;21:3428‐3435. https://doi.org/10.1158/1078‐
0432.CCR‐14‐3253
21. Laurent C, Charmpi K, Gravelle P, et al. Several immune escape
patterns in non‐Hodgkin's lymphomas. Oncoimmunology. 2015;4:
e1026530. https://doi.org/10.1080/2162402X.2015.1026530
22. Myklebust JH, Irish JM, Brody J, et al. High PD‐1 expression and
suppressed cytokine signaling distinguish T cells infiltrating follicular
lymphoma tumors from peripheral T cells. Blood. 2013;121:1367‐
1376. https://doi.org/10.1182/blood‐2012‐04‐421826
23. Zhang W, Huang Q, Xiao W, et al. Advances in anti‐tumor treat-
ments targeting the CD47/SIRPαaxis. Front Immunol. 2020;11:18.
https://doi.org/10.3389/fimmu.2020.00018
24. Fowler NH, Nastoupil L, De Vos S, et al. The combination of ibrutinib
and rituximab demonstrates activity in first‐line follicular lymphoma.
Br J Haematol. 2020;189:650‐660. https://doi.org/10.1111/bjh.
16424
25. Valero JG, Matas‐Cespedes A, Rodriguez V, et al. The receptor of
the colony‐stimulating factor‐1 (CSF‐1R) is a novel prognostic factor
and therapeutic target in follicular lymphoma. Leukemia. 2021.
https://doi.org/10.1038/s41375‐021‐01201‐9
How to cite this article: Araujo‐Ayala F, Pérez‐Galán P,
Campo E. Vulnerabilities in the tumor and microenvironment
in follicular lymphoma. Hematological Oncology.
2021;39(S1):83–87. https://doi.org/10.1002/hon.2855
ARAUJO‐AYALA ET AL.
-
87
Received: 26 February 2021
DOI: 10.1002/hon.2852
SUPPLEMENT ARTICLE
Upfront identification of high‐risk follicular lymphoma
Carla Casulo
Department of Medicine, Division of
Hematology and Oncology, Wilmot Cancer
Institute, Rochester, New York, USA
Correspondence
Carla Casulo, Department of Medicine,
Division of Hematology and Oncology, Wilmot
Cancer Institute, 601 Elmwood Avenue Box
704, Rochester, NY 14642, USA.
Email: Carla_casulo@urmc.rochester.edu
Abstract
Follicular lymphoma (FL) is a common disease with clinically indolent behavior, and
a long natural history for the majority of patients. Despite excellent therapeutic
strategies currently available for FL, approximately 10%–20% of patients will
experience early disease progression, defined as occurring within two years of
diagnosis. These patients have poor outcomes, with overall survival at 5 years
ranging between 37% and 50%. Much of the biology driving early progression and
inferior survival is attributed to early transformation events; however, trans-
formation alone does not account for all the observed clinical heterogeneity and
survival differences among patients. Several clinical, genetic, and molecular alter-
ations in FL have been discovered that help define subsets of patients at risk for
multiply relapses and refractory disease, and are slowly making their way into risk
calculators to be used in daily practice. Additionally, the role of functional imaging
with PET scan, as well as circulating and cell free tumor DNA are being evaluated as
tools to define high‐risk subsets of patients with FL. This review seeks to provide an
over view of current and evolving biomarkers that define high‐risk FL at diagnosis.
The goal is for these tools to assist clinicians in integrating these rapidly evolving
prognosis models into clinical practice, in the hopes of risk‐stratifying treatments
and improving outcomes for patients.
KEYWORDS
follicular lymphoma, high‐risk disease, relapse
1
|
INTRODUCTION
Follicular lymphoma (FL) arises from precursor B cells that acquire
the t(14;18), undergo additional genetic alterations, and develop
malignant transformation within the germinal center of the lymph
node.
1
Affecting approximately 2–4 people per 100,000 person‐
years, FL is the most common indolent lymphoma diagnosed in the
United States and Europe.
2
On a global scale, the incidence of FL
appears to be rising in developed countries, suggesting possible
environmental contributions affecting pathobiology and genetic
susceptibility. FL is described as clinically and biologically heteroge-
nous, owing to rare morphologic FL subtypes including pediatric type
and duodenal type FL variants, and distinct clinical behavior leading
to divergent outcomes in ∼20% of cases.
3
FL clinical behavior is generally indolent, where 80% of patients
experience long‐term disease control following standard chemo‐
immunotherapy combinations. However, 20% or so of cases experi-
encing early disease progression have poor outcomes (5 years overall
survival [OS] of 35%–50%).
4
An additional subset of patients are
refractory to both anti‐CD20 antibodies and alkylators (so called
“double refractory”), have continuous relapses over time, or undergo
transformation to aggressive histology. These patients do not enjoy
the long natural history of FL with median OS of nearly 2 decades
and are often designated as “high risk,” owing to a more aggressive
clinical phenotype and less favorable outcomes.
5
Identifying patients with high‐risk FL upfront is a global research
effort aimed at minimizing risk of death, histologic transformation,
and optimizing duration of treatment response to ease suffering and
88
-
Hematological Oncology. 2021;39(S1):88–93. wileyonlinelibrary.com/journal/hon © 2021 John Wiley & Sons Ltd.
morbidity from this disease. The subject of this review is to discuss
current biomarkers and those in development that can aide in iden-
tifying high‐risk FL.
1.1
|
Current biomarkers identifying high‐risk
patients
Over the last several years, the discovery of novel clinical and
biologic markers has revolutionized FL disease prognostication and
risk precision.
6
However, despite well‐established clinical calcula-
tors and molecular classifiers, the precise utilization of these tools
remains in question as it relates to selection of therapy at diagnosis
or relapse. When discussing biomarkers and their utilization to
identify subsets of patients with high‐risk disease, it is relevant to
define the differences between prognostic and predictive markers.
7
Prognostic biomarkers appraise risk of a particular outcome such as
disease progression or death. Prognostic markers can assist in
developing risk‐adapted treatments. In contrast, predictive bio-
markers are reserved to associate a specific therapy with a
particular clinical response, or lack thereof. As such, identifying
disease response to specific therapies is enhanced with predictive
biomarkers. Complicating matters is that in many cases, some bio-
markers are both prognostic and predictive. In FL, the most well
established prognostic markers of outcome include clinical calcula-
tors such as the FLIPI or FLIPI‐2, histologic variations such as grade,
disease‐specific markers such as tumor burden and stage, and sur-
rogates for tumor kinetics such as early progression of disease
(POD24). Molecular markers such as the presence of somatic mu-
tations, and differential expression of genes within and outside the
FL tumor microenvironment, are gaining widespread attention as
critical determinants of disease outcome. Many studies have
established that functional imaging with PET at the end of therapy
also predicts both progression free (PFS) and overall survival (OS)
irrespective of treatment.
1.2
|
Clinical risk calculators
The FL International Prognostic Index (FLIPI) is the most commonly
used clinical calculator to determine FL prognosis.
8
The FLIPI's five
pretreatment patient characteristics (nodal sites, lactate dehydro-
genase, age >60 years, Stage III‐IV, and hemoglobin <12 g/dl) were
strongly prognostic of OS in over 900 patients with low‐grade FL
treated with chemotherapy (no immunotherapy) strongly associated
with 5‐and 10‐year OS based on low, intermediate risk, or high‐risk
designation (Table 1). In a retrospective analysis of rituximab treated
patients by the German Low Grade Lymphoma Study Group (GLSG),
patients with high‐risk FLIPI had inferior time to treatment failure
(67% at 2 years) compared to those with intermediate risk and low‐
risk FLIPI groups (90% and 92%, respectively).
9
Similarly, The Na-
tional LymphoCare Study, a prospective, multicenter observational
cohort of patients with FL in the United States including nearly 70%
of rituximab treated patients, observed a hazard ratio for OS higher
in the high‐risk FLIPI group compared to the intermediate risk FLIPI
groups.
10
The FLIPI 2 calculator was another method used to predict PFS
upfront using additional parameters such as increased beta 2
microglobulin (B2M) and bone marrow involvement, and had com-
parable predictive ability as the FLIPI.
11
When attempting to spe-
cifically identify patients with POD24, data using the FLIPI and FLIP2
are more limited; however, a study by Jurinovic et al.
12
reported a
sensitivity between 70% and 78%, and a specificity of 56%–58%,
suggesting a heterogeneity among the POD24 patients that is inad-
equately captured by this prognostic index.
Other clinical indices have attempted to capture high‐risk pa-
tients, by using a parsimonious mode incorporating only bone
marrow involvement and B2M level.
13
The PRIMA‐PI initially
included patients from the randomized PRIMA study of patients
treated with chemoimmunotherapy, with or without rituximab
maintenance. High‐risk patients had elevated B2M greater than
3 mg/L and had 5‐year PFS of only 37%. Other groups validated the
utility of the PRIMA ‐PI in chemotherapy‐free approaches using
immunomodulator lenalidomide on the RELVANCE study, and using
rituximab and interferon in the Nordic Lymphoma Group studies. The
PRIMA‐PI was not able to sufficiently discriminate patients treated
with lenalidomide, but did identify a high‐risk group of patients with
FL experiencing shortened OS and time to treatment failure. While
authors did not explicitly evaluate the PRIMA to assess POD24,
there was no difference in transformation rates between both
groups, and they did find improved risk stratification compared to the
FLIPI, especially in patients older than 60 years.
14
The FLEX calculator was developed from patients treated on the
phase 3 GALLIUM trial (NCT01332968) using Obinutuzumab based
chemoimmunotherapy combinations in previously untreated
advanced FL. This novel prognostic model sough to identify high‐risk
patients compared to FLIPI, FLIPI‐2, and PRIMA‐PI. The primary
endpoint was PFS but OS and risk of POD24 were evaluated. It
included nine clinical factors (male sex, sum of the product diameter
[SPD] in the highest quartile, Grade 3A histology, >2 extranodal sites,
ECOG PS >1, hemoglobin <12 g/dl, elevated B2M, elevated LDH,
and peripheral blood absolute natural killer cell count <100/μl).
15
The model was validated in the SABRINA trial (randomized
Phase 3 trial of subcutaneous rituximab vs. intravenous rituximab for
first‐line FL treatment; NCT01200758). Low‐risk patients had zero to
two factors; and high‐risk patients had three to nine factors. PFS at 3
years was 86% for high‐risk patients and 68% for low‐risk patients.
Using FLEX, the sensitivity for a high‐risk score to predict POD24
was 60%, versus 53% for FLIPI and FLIPI‐2, and 69% for PRIMA‐PI.
Specificity for POD24 was 68% with FLEX compared with 59% for
FLIPI and FLIPI‐2, and 47% for PRIMA‐PI (Table 1).
Compared to other frequently used clinical prognostic calcula-
tors, the FLEX appeared to have greater accuracy for predicting
POD24, particularly with novel immunotherapy combinations, and
the first prognostic score in FL developed in patients treated with
bendamustine‐and obinutuzumab‐based regimens.
CASULO
-
89
1.3
|
Impact of the tumor microenvironment on
identifying high‐risk FL
The microenvironment surrounding FL tumor cells (tumor micro-
environment [TME]) is a critically influential component of FL
tumorigenesis and clinical behavior. In 2004, the Leukemia and
Lymphoma Molecular Profiling Project described pivotal findings
using gene expression profiling on biopsy samples from patients
treated in the prerituximab era.
16
Two combinations of gene
expression were assessed for ability to predict survival, where
increased expression of genes in T‐cells and macrophages had a
more favorable prognosis (relative risk of death 0.15). In com-
parison, increased expression of genes from macrophages or
dendritic cells had higher risk disease, with an unfavorable prog-
nosis (relative risk of death 9.35). Subsequent studies have been
unable to consistently reproduce this same impact of the immune
system's effect of FL prognosis, largely due to heterogeneously
treated patient populations and study small sizes. Kridel et al.
17
reported on the adverse prognostic impact of CD163 +macro-
phages, only in patients treated with rituximab and cyclophos-
phamide, vincristine, prednisone (R‐CVP), but not rituximab with
cyclophosphamide, doxorubicin, vincristine, and prednisone (R‐
CHOP). Similarly, other studies assessing the impact of number,
distribution, and frequency of tumor‐associated macrophages and
tumor‐associated T cells have resulted in inconsistent conclusions
on FL prognosis.
TABLE 1Prognostic calculators in follicular lymphoma
Risk model Factors Risk groups Prognostic impact
Sensitivity of
high‐risk group
for predicting
POD24
Specificity of
high‐risk group
for predicting
POD24
FLIPI ‐Age >60
‐Stage III‐IV
‐Hg <12 g/dl
‐Elevated LDH
‐>Four nodal sites
Low risk(0–1 points) 91% 5‐year OS 53%–78% 56%–62%
Intermediate risk(2 points) 78% 5‐year OS
High risk(3 or more points) 53% 5‐year OS
FLIPI2 ‐Age >60
‐Bone marrow
involvement
‐Hg <12 g/dl
‐Elevated β2
microglobulin
‐Mass >6 cm
Low risk(0–1 points) 80% 5‐year OS 53% 59%–76%
Intermediate risk(2 points) 51% 5‐year OS
High risk(3 or more points) 19% 5‐year OS
PRIMA‐PI ‐ β2 microglobulin >3g/L
‐Bone marrow
involvement
Low risk(0 points) 69% 5‐year PFS 69% 48%
Intermediate risk(1 point) 55% 5‐year PFS
High risk(2 points) 37% 5‐year PFS
FLEX ‐Male sex
‐SPD in the highest
quartile
‐Histologic grade 3A
‐>2 extranodal sites
‐ECOG PS >1
‐Hg <12 g/dl
‐Elevated β2
microglobulin
‐NK cell count >100/μl
‐Elevated LDH
Low risk(0–2 points) 86% 3‐year PFS 60% 68%
High risk(3–9 points) 68% 3‐year PFS
M7‐FLIPI ‐ECOG PS >1
‐FLIPI high risk
‐Mutations in EP300,
CREBBP, CARD11,
MEF2B, EZH2,
ARID1A, FOXO1
Low risk 68%–77% 5‐year FFS 43%–61% 77%–86%
High risk 22%–38% 5‐year FFS
POD24‐PI ‐ECOG PS >1
‐FLIPI high risk
‐Mutations in EP300,
EZH2, FOXO1
Low risk 72%–77% 5‐year FFS 54%–78% 67%–73%
High risk 36%–50% 5‐year FFS
Tumor
microenvironment
PDL‐2 expression Immune infiltration
LO
– Not reported Not reported
Immune infiltration
HI
–
90
-
CASULO
To identify the role of the TME in predicting the risk of POD24,
Tobin et al.
18
recently targeted gene sequencing using NanoString
technology from paraffin embedded tissue and multispectral immu-
nofluorescence on a tissue microarray, and applied them to two
groups: a discovery cohort of 132 patients from Princess Alexandria
Hospital with early and advanced staged follicular lymphoma who
received either chemotherapy or observation, and two independent
validation cohorts of 198 patients with advanced stage disease
treated with RCHOP and RCVP from the German low‐grade lym-
phoma study group and the British Columbia Cancer Agency. They
also performed T cell repertoire analysis, flow cytometry, immuno-
fluorescence, and next generation sequencing. Gene expression
profiling revealed distinct clustering of follicular lymphoma samples
based on high or low expression of immune infiltrating cells. Low
expression of certain immune markers (including PDL‐2, TNF‐α, CD4,
and CD68) were all associated with poor outcome; however, the
most specific marker with the highest specificity and sensitivity was
PD‐L2. They then dichotomized PD‐L2 expression into immune
infiltration “high” and “immune infiltration low” in subsequent ana-
lyses. PD‐L2 is an immune checkpoint present broadly on both tumor
cells and the tumor microenvironment. To localize its distribution,
they performed flow cytometry in fresh FL samples, and quantified
PDL2 expression by PCR. They identified that PD‐L2 gene expression
was distributed in both CD20+tumor cells as well as non CD20+
cells in the tumor microenvironment. However, the proportion of
PDL2 was lower in the CD20+cells. Overall there was lower
expression of all immune cells in the immune infiltration low
phenotype compare to the immune infiltration high phenotype. When
testing the relevance of immune infiltration and POD24, they found
that POD24 events in the Princess Alexandria discovery set were
more enriched for the immune infiltration low phenotype. These
findings were also validated in the British Columbia cancer agency
and German lymphoma study group populations. Nearly 50% of pa-
tients with low PD‐L2 had POD24 events compared to 16% in those
with high PD‐L2, concluding that low PD‐L2 identifies a subset of
patients enriched for POD24.
18
1.4
|
Somatic mutations, gene expression profiling,
and clinic‐pathologic models
Toward a precision approach, investigators from the GLSG harmo-
nized clinical and pathologic data to create a clinico‐genetic risk
model aimed at more accurate risk prognostication in patients
receiving front line chemoimmunotherapy.
19
They performed deep
DNA sequencing from formalin fixed pretreatment biopsies to
analyze the mutational status of genes in 151 patients with follicular
lymphoma tumor samples. The resulting prognostic tool, called the
m7‐FLIPI, distilled down 74 genes into seven genes with nonsilent
mutations occurring at a variant allele frequency of 10% or greater,
and combined these with high‐risk FLIPI status and ECOG perfor-
mance status. These included genes that increased risk of progres-
sion, including EP300, FOX01, CREBBP, CARD11, and those that
decreased risk of progression, including EZH2, ARID1A, and MEF2B.
The cumulative risk score was calculated by combining relative
weights of these genes in a multivariate analysis predicting failure‐
free survival. This m7‐FLIPI score was tested to identify POD24
but only captured about 50% of patients as high risk. Jurinovic et al.
12
later developed the POD24‐PI, designed to augment the sensitivity
and specificity of the m7‐FLIPI in early progressing patients. This
model included only three genes, including EP300, FOX01, and EZH2,
performance status, and FLIPI score. The POD24‐PI was more sen-
sitive at identifying POD24 patients but did not outperform other
metrics due to lower specificity.
12
A recently developed prognostic model, termed the Bio‐FLIPI,
integrated intrafollicular CD4 expression with FLIPI to improves
identification of FL patients at risk for early treatment failure.
Mondello et al.
20
evaluated 496 patients using tissue microarrays for
CD4, CD8, FOXP3, CD32b, CD14, CD68, CD70, SIRPa, TIM3, PD‐1,
and PDL1. They found CD4, CD8, FOXP3, PD‐1, and SIRPαwere
associated with risk of early failure and were subsequently evaluated
in the validation set; however, only intrafollicular CD4 expression
remained significant in multivariate analysis. Lack of intrafollicular
CD4 expression was associated with higher risk of early failure in
both the discovery and validation cohorts, with a pooled OR =2.29
(95% CI 1.47–3.58; p<0.001). The BioFLIPI then combined CD4
intrafollicular expression and FLIPI into a one‐to‐four scale and was
robustly associated with risk of early failure.
20
Gene expression signatures beyond those identified in the TME
have clinical utility on the upfront identification of patients with poor
outcomes in FL. While not yet ready for standard use, these molec-
ular signatures are highly promising for further investigation. Huet
et al.
21
performed a large‐scale gene expression profiling study using
samples from 160 untreated FL patients from the PRIMA study in FL
to establish define correlates of PFS and early treatment failure. The
authors identified 23 genes associated with the TME and B‐cell
biology. These were strongly associated with disease progression
based on a score of low risk or high risk. Further adjusting for clinical
prognostic tools such as the FLIPI, use of maintenance rituximab, the
gene signature sustained its predictive utility.
21
This method pre-
dicted POD24 with a sensitivity of 43% and a specificity of 79%.
1.5
|
PET‐based functional imaging biomarkers
Metabolic assessment of FL disease burden is considered standard of
care following first‐line chemoimmunotherapy. It is well established
that attainment of complete metabolic response on a five‐point scale
(ref) is highly prognostic of outcome, regardless of treatment used. A
pooled analysis of European patients treated on three prospective
clinical trials established that a positive PET scan (defined as Deau-
ville score of 4 or 5) following front‐line treatment was highly
prognostic of both PFS and OS.
22
A novel method of metabolic ac-
tivity has gaining attention is total metabolic tumor volume (TMTV).
Defined as a cut off of 510 cm
3
or greater, high TMTV at diagnosis is
associated with a poor prognosis.
23
When combined with circulating
CASULO
-
91
tumor cells and cell free DNA, TMTV at diagnosis has also been
strongly correlated with inferior PFS.
24
2
|
WHAT ARE HOPES FOR THE FUTURE TO
IDENTIFY HIGH‐RISK FL UP FRONT?
2.1
|
Implementation of biomarkers into clinical
practice
There are currently a multitude of clinical, molecular, clinic‐
pathologic, and functional imaging based biomarkers that can group
patients with FL into several risk categories at the time of diagnosis.
These tools do not yet inform on how best to treat patients, which
remains a significant limitation to day‐to‐day practical implementa-
tion. Additional research is needed to integrate these important de-
velopments in clinically meaningful ways. A promising strategy may
involve use minimal residual disease (MRD) testing with circulating
tumor‐or cell‐free DNA. This has been used by Delfaue‐Larue and
colleagues in combination with TMTV to identify groups of patients
with FL at risk of poor outcomes (PFS of 65% at 4 years). Several
other studies demonstrate value in MRD assessment after chemo-
immunotherapy as high prognostic of end of treatment outcome, and
others also determine high levels of circulating tumor DNA as asso-
ciated with poor PFS.
24
Use of predictive markers will be especially relevant as the
design of precision, risk adapted therapies are developed. Gain of
function mutations in enhancer of zeste homolog 2 (EZH2) are
associated with favorable outcome in FL and occur in approximately
20% of individuals. The first in class oral inhibitor of EZH2 tazeme-
tostat was recently approved by the United States Food and Drug
Administration for patients with FL having an EZH2 mutation or
those with no other treatment options available. EZH2 mutation in Fl
diagnostic samples has been shown to be a favorable prognostic
marker; and also appears to be correlate with response to therapy. In
the pivotal Phase 2 study, patients harboring mutation in EZH2 had
higher objective response rates compared to patients with wild type
EZH2 (69% vs. 35%).
25
Moreover, a recent publication by Jurinovic
et al.
26
suggested that patients with an EZH2 mutation had a longer
PFS if they were treated with CHOP or CVP in the frontline setting
versus bendamustine‐based therapy.
We look forward to the opportunity to risk adapt therapy by using
precision approaches for patient with FL. These and other studies
support the optimism that the ability to do so is on the horizon.
CONFLICT OF INTEREST
Carla Casulo received research funding from Gilead, BMS, and
Genentech.
REFERENCES
1. Carbone A, Roulland S, Gloghini A, et al. Follicular lymphoma. Nat
Rev Dis Primers. 2019;5(1):83. https://doi.org/10.1038/s41572‐019‐
0132‐x.
2. Teras LR, DeSantis CE, Cerhan JR, Morton LM, Jemal A, Flowers CR.
US lymphoid malignancy statistics by World Health Organization
subtypes. CA Cancer J Clin. 2016;66:443‐459. https://doi.org/10.
3322/caac.21357.
3. Swerdlow SH, Campo E, Pileri SA, et al. The 2016 revision of the
World Health Organization classification of lymphoid neoplasms.
Blood. 2016;127(20):2375‐2390. https://doi.org/10.1182/blood‐
2016‐01‐643569.
4. Casulo C, Day B, Dawson KL, et al. Disease characteristics, treat-
ment patterns, and outcomes of follicular lymphoma in patients 40
years of age and younger: an analysis from the National Lymphocare
Study. Ann Oncol. 2015;26(11):2311‐2317. https://doi.org/10.1093/
annonc/mdv375.
5. Casulo C, Nastoupil L, Fowler NH, Friedberg JW, Flowers CR. Unmet
needs in the first‐line treatment of follicular lymphoma. Ann Oncol.
2017;28(9):2094‐2106. https://doi.org/10.1093/annonc/mdx189.
6. Welaya K, Casulo C. Follicular lymphoma: redefining prognosis,
current treatment options, and unmet needs. Hematology/Oncology
Clinics of North America. 2019:33;627‐638. https://doi.org/10.1016/j.
hoc.2019.03.003.4
7. Henry NL, Hayes DF. Cancer biomarkers. Mol Oncol. 2012;6(2):
140‐146. https://doi.org/10.1016/j.molonc.2012.01.010.
8. Solal‐Celigny P, Roy P, Colombat P, et al. Follicular lymphoma in-
ternational prognostic index. Blood. 2004;104(5):1258‐1265. https://
doi.org/10.1182/blood‐2003‐12‐4434.
9. Buske C, Hoster E, Dreyling M, Hasford J, Unterhalt M,
Hiddemann W. The Follicular Lymphoma International Prognostic
Index (FLIPI) separates high‐risk from intermediate‐or low‐risk
patients with advanced‐stage follicular lymphoma treated front‐
line with rituximab and the combination of cyclophosphamide,
doxorubicin, vincristine, and prednisone (R‐CHOP) with respect to
treatment outcome. Blood. 2006;108(5):1504‐1508. https://doi.org/
10.1182/blood‐2006‐01‐013367.
10. Nooka AK, Nabhan C, Zhou X, et al. Examination of the follicular
lymphoma international prognostic index (FLIPI) in the National
LymphoCare study (NLCS): a prospective US patient cohort treated
predominantly in community practices. Ann Oncol. 2013;24(2):
441‐448. https://doi.org/10.1093/annonc/mds429.
11. Federico M, Bellei M, Marcheselli L, et al. Follicular lymphoma in-
ternational prognostic index 2: a new prognostic index for follicular
lymphoma developed by the international follicular lymphoma
prognostic factor project. J Clin Oncol. 2009;27(27):4555‐4562.
https://doi.org/10.1200/JCO.2008.21.3991.
12. Jurinovic V, Kridel R, Staiger AM, et al. Clinicogenetic risk models
predict early progression of follicular lymphoma after first‐line
immunochemotherapy. Blood. 2016;128(8):1112‐1120. https://doi.
org/10.1182/blood‐2016‐05‐717355.
13. Bachy E, Maurer MJ, Habermann TM, et al. A simplified scoring
system in de novo follicular lymphoma treated initially with immu-
nochemotherapy. Blood. 2018;132:49. https://doi.org/10.1182/
blood‐2017‐11‐816405.
14. Kimby E, Lockmer S, Holte H, et al. The simplified follicular lym-
phoma PRIMA‐prognostic index is useful in patients with first‐line
chemo‐free rituximab‐based therapy. Br J Haematol. 2020;191:738.
https://doi.org/10.1111/bjh.16692.
15. Mir F, Mattiello F, Grigg A, et al. Follicular Lymphoma Evaluation
Index (FLEX ): a new clinical prognostic model that is superior
to existing risk scores for predicting progression‐free survival
and early treatment failure after frontline immunochemotherapy.
Am J Hematol. 2020;95(12):1503‐1510. https://doi.org/10.1002/ajh.
25973.
16. Dave SS, Wright G, Tan B, et al. Prediction of survival in follicular
lymphoma based on molecular features of tumor‐infiltrating immune
cells. N Engl J Med. 2004;351(21):2159‐2169. https://doi.org/10.
1056/NEJMoa041869.
92
-
CASULO
17. Kridel R, Xerri L, Gelas‐Dore B, et al. The prognostic impact of
CD163‐positive macrophages in follicular lymphoma: a study from
the BC cancer agency and the lymphoma study association. Clin
Cancer Res. 2015;21(15):3428‐3435. https://doi.org/10.1158/1078‐
0432.CCR‐14‐3253.
18. Tobin JWD, Keane C, Gunawardana J, et al. Progression of disease
within 24 months in follicular lymphoma is associated with reduced
intratumoral immune infiltration. J Clin Oncol. 2019;37(34):
3300‐3309. https://doi.org/10.1200/JCO.18.02365.
19. Pastore A, Jurinovic V, Kridel R, et al. Integration of gene mutations
in risk prognostication for patients receiving first‐line immunoche-
motherapy for follicular lymphoma: a retrospective analysis of a
prospective clinical trial and validation in a population‐based regis-
try. Lancet Oncol 2015;16:1111‐1122. https://doi.org/10.1016/
S1470‐2045(15)00169‐2.
20. Mondello P, Fama A, Larson MC, et al. Intrafollicular CD4+T‐cells as
an independent predictor of early clinical failure in newly diagnosed
follicular lymphoma. 2019;134(suppl_1):121.
21. Huet S, Tesson B, Jais JP, et al. A gene‐expression profiling score for
prediction of outcome in patients with follicular lymphoma: a
retrospective training and validation analysis in three international
cohorts. Lancet Oncol. 2018;19:549‐561. https://doi.org/10.1016/
S1470‐2045(18)30102‐5.
22. Trotman J, Luminari S, Boussetta S, et al. Prognostic value of PET‐CT
after first‐line therapy in patients with follicular lymphoma: a pooled
analysis of central scan review in three multicentre studies. Lancet
Haematol. 2014;1(1):e17‐e27. https://doi.org/10.1016/S2352‐3026
(14)70008‐0.
23. Meignan M, Cottereau AS, Versari A, et al. Baseline metabolic tumor
volume predicts outcome in high‐tumor‐burden follicular lymphoma:
a pooled analysis of three multicenter studies. J Clin Oncol.
2016;34:3618. https://doi.org/10.1200/JCO.2016.66.9440.
24. Delfau‐Larue M‐H, van der Gucht A, Dupuis J, et al. Total metabolic
tumor volume, circulating tumor cells, cell‐free DNA: distinct prog-
nostic value in follicular lymphoma. Blood Adv. 2018;2(7):807‐816.
https://doi.org/10.1182/bloodadvances.2017015164.
25. Morschhauser F, Tilly H, Chaidos A, et al. Tazemetostat for patients
with relapsed or refractory follicular lymphoma: an open‐label, single‐
arm, multicentre, phase 2 trial. Lancet Oncol. 2020;21(11):1433‐1442.
https://doi.org/10.1016/S1470‐2045(20)30441‐1.
26. Jurinovic V, Passerini V, Oestergaard MZ, et al. Evaluation of the
m7‐FLIPI in patients with follicular lymphoma treated within the
Gallium trial: EZH2 mutation status may be a predictive marker for
differential efficacy of chemotherapy. Blood. 2019;134(suppl_1):122.
https://doi.org/10.1182/blood‐2019‐130208.
How to cite this article: Casulo C. Upfront identification of
high‐risk follicular lymphoma. Hematological Oncology.
2021;39(S1):88–93. https://doi.org/10.1002/hon.2852
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Received: 26 February 2021
DOI: 10.1002/hon.2853
SUPPLEMENT ARTICLE
High‐risk follicular lymphoma: Treatment options
Brad Kahl
1,2
1
Medicine, Washington University in St. Louis,
St. Louis, Missouri, USA
2
Lymphoma Program, Siteman Cancer Center,
St. Louis, Missouri, USA
Correspondence
Brad Kahl, Medicine, Washington University
in St. Louis, St. Louis, Missouri, USA.
Email: bkahl@wustl.edu
Abstract
Follicular lymphoma (FL) is the most common indolent non‐Hodgkin lymphoma in
the Western hemisphere. The natural history of FL appears to have been favor-
ably impacted by the introduction of rituximab. Randomized clinical trials have
demonstrated that the addition of rituximab to standard chemotherapy induction
has improved the overall survival. Maintenance rituximab strategies can improve
progression‐free survival (PFS). Obinutuzumab was superior to rituximab for PFS
in the GALLIUM study, although the benefit was small and required more drug.
Chemotherapy platforms have changed in the past decade, as bendamustine
combined with rituximab has become commonly utilized frontline strategy in
North America and parts of Europe, although there is certainly no one standard
treatment. However, several unmet needs remain, including a better ability to
identify high‐risk patients at diagnosis, the development of predictive biomarkers
for targeted agents, the development of novel combinations, and strategies to
reduce the risk of transformation. A multitude of novel therapies are under
investigation in both the frontline and relapsed/refractory settings. It will be
critical to identify the most appropriate populations for new agents and to
develop validated surrogate endpoints, so that novel agents can be tested (and
adopted, if appropriate) efficiently.
KEYWORDS
follicular lymphoma, high‐risk, therapy
1
|
THERAPY OF SYMPTOMATIC, HIGH‐TUMOR
BURDEN FOLLICULAR LYMPHOMA
The addition of rituximab to conventional chemotherapy, has
improved outcomes in follicular lymphoma (FL), including overall
and complete response rates, progression‐free survival (PFS) and
overall survival (OS). The results were remarkably consistent across
four randomized clinical trials. Clearly, rituximab added to chemo-
therapy has a therapeutic advance in FL. However, newer data
raises questions regarding the optimal anti‐CD20 monoclonal
antibody and the optimal chemotherapy backbone remains
unsettled.
2
|
WHICH ANTI‐CD20 MONOCLONAL
ANTIBODY IS BEST?
The landmark GALLIUM trial compared obinutuzumab, a glyco‐
engineered type II anti‐CD20 monoclonal antibody against ritux-
imab in the frontline management of high‐tumor burden FL.
1
The
study randomly assigned more than 1200 patients across the globe
to either six cycles of either obinutuzumab +chemotherapy or rit-
uximab +chemotherapy, followed by maintenance anti‐CD20 for 2
years. Each participating center selected a chemotherapy backbone,
with the option of bendamustine, cyclophosphamide, adriamycin,
vincristine, prednisone (CHOP), or CVP. The rates of chemotherapy
94
-
Hematological Oncology. 2021;39(S1):94–99. wileyonlinelibrary.com/journal/hon © 2021 John Wiley & Sons Ltd.
use were approximately 60% for bendamustine, 30% for CHOP, and
10% for CVP. The trial demonstrated a statistically significant
reduction in the risk for progression or death in the patients assigned
to obinutuzumab +chemotherapy. The hazard ratio was 0.66, which
equates to a 34% risk reduction. At the landmark of 3 years, 80% of
the obinutuzumab +chemotherapy patients were in remission versus
73% of the rituximab +chemotherapy patients. No OS differences
were observed. The obinutuzumab‐treated patients had slightly more
infusion reactions, episodes of cytopenia, and infections than the
rituximab‐treated patients. So is obinutuzumab a superior anti‐CD20
monoclonal antibody? Certainly, the outcome of PFS was certainly
better in the obinutuzumab‐treated patients. However, the results
must be interpreted in the context of the dose and schedule. Patients
received higher doses of obinutuzumab and more doses of obinutu-
zumab. A patient who is 2 m
2
would receive 36% more obinutuzumab
than rituximab on this study. Note the ∼35% risk reduction is very
similar to the ∼35% difference in dosing. As a result of the design
issues with GALLIUM, it is impossible to know if obinutuzumab is
truly a better monoclonal antibody than rituximab in FL or whether
the results observed are simply of function of dosing differences. As a
result, obinutuzumab has not been universally accepted as the new
standard of care and some investigators continue to administer
rituximab.
3
|
WHICH CHEMOTHERAPY IS THE BEST?
Before the introduction of bendamustine, the most commonly used
regimens in the United States were R‐CHOP (rituximab, cyclophos-
phamide, vincristine, prednisone) (60%), R‐CVP (rituximab, cyclo-
phosphamide, prednisone) (27%), and R‐fludarabine‐based regimen
(13%). A randomized comparison of these regimens indicated R‐
CHOP had the best risk‐benefit profile of the three, as it was more
active than R‐CVP and less toxic than R‐FM.
2
The alkylating agent bendamustine has gained widespread,
although not universal, adoption as the chemotherapy platform of
choice in FL. A phase III trial from the StIL group comparing bend-
amustine, rituximab (BR) to R‐CHOP demonstrated BR had better
efficacy and reduced toxicity. In this multicenter phase III study, 549
patients with high‐tumor burden indolent non Hodgkin lymphoma
(NHL) and mantle cell lymphoma (MCL) (median age 64 years) were
randomized to receive bendamustine 90 mg/m
2
on days 1 and 2, with
rituximab 375 mg/m
2
on day 1, every 28 days (the BR group) or to
receive standard R‐CHOP chemotherapy every 21 days. The overall
response rates (ORRs) were similar in the BR versus R‐CHOP groups
(92.7% vs. 91.3%, respectively), but the complete response (CR) rate
was significantly higher in the BR group (39.8%) compared with the
R‐CHOP group (30.0%) (p=0.03). When evaluating just the FL pa-
tients, with a median follow‐up of 45 months, the median PFS was
significantly longer after BR compared with R‐CHOP (median PFS,
not reached vs. 40.9 months, p=0.007). OS did not differ between
both groups. There were less hematologic toxicity, alopecia, in-
fections, peripheral neuropathy, and stomatitis with BR. Drug‐
associated erythematous skin reactions were seen more frequently
in the BR group. These data suggest that BR is a better option for
untreated high‐tumor burden FL. Nine‐year updates from this trial
were presented at the 2017 American Society of Clinical Oncology
Meetings.
3
The long‐term follow‐up indicated the PFS benefit per-
sisted over time but no OS benefit emerged.
A confirmatory randomized phase III trial (BRIGHT study) was
conducted in North America. Previously untreated indolent NHL
patients with high‐tumor burden were randomized to BR or R‐
CHOP/R‐CVP. Control arm patients were identified as an R‐CHOP or
R‐CVP candidate prior to randomization. The primary endpoint was
to show noninferiority of BR in the CR rate. Seventy percent of the
447 enrolled patients had FL, and in these patients, BR therapy was
found to be noninferior to the R‐CHOP/R‐CVP control arm for CR
rate (30% vs. 25%) and the ORR (99% vs. 94%). Side‐effect profiles
were distinct, with more GI toxicity and rash with BR, and more
neuropathy and alopecia with R‐CHOP/R‐CVP. Long‐term follow‐up
was reported in 2019.
4
When one separates out the mantle cell
lymphoma patients and limits the analysis to indolent lymphoma, BR
was not statistically superior to R‐CHOP/R‐CVP for PFS, although
there was trend toward improvement in PFS with BR with a hazard
ratio of 0.70 (95% CI: 0.49–1.01). Although, the BRIGHT data do not
exactly replicate the StIL data for BR, they do suggest that BR re-
mains an attractive alternative to R‐CHOP or R‐CVP in FL.
4
|
WHO SHOULD RECEIVE MAINTENANCE ANTI‐
CD20 THERAPY?
The question of whether to administer maintenance rituximab after
frontline R‐chemotherapy was addressed in the phase III PRIMA trial.
The study evaluated the efficacy and safety profile of maintenance
rituximab in newly diagnosed FL patients who responded to initial
treatment with rituximab plus chemotherapy. Induction treatment
was selected by center; R‐CHOP (75%), R‐CVP (22%), or R‐FCM
(3%). Patients were randomized to either observation or a single
dose of rituximab every 2 months for 2 years. At a median follow‐up
of 36 months from randomization, the 2‐year PFS in the maintenance
rituximab arm was 75% versus 58% in the observation arm
(p<0.0001). The beneficial effect of maintenance rituximab was seen
irrespective of the induction chemotherapy backbone and in both CR
and partial remission (PR) patients. Grade 3–4 adverse events were
slightly higher in the maintenance rituximab arm (24% vs. 17%).
Long‐term follow‐up from this dataset was published recently.
5
With
a median follow‐up of 9 years, the 10‐year PFS estimates were 51.1%
in the rituximab maintenance arm and 35.0% in the no maintenance
arm. No difference in OS was observed, with both groups exhibiting
an OS of 80% at 10 years. No new safety signals emerged. Given the
lack of OS benefit, the decision regarding the use of maintenance
rituximab can be individualized, but a 50% likelihood of remaining
disease free at 10 years is highly appealing and begs the question of
whether a proportion of FL patients are actually being cured with
frontline therapy.
KAHL
-
95
5
|
WHAT ABOUT MAINTENANCE ANTI‐CD20
THERAPY AFTER BENDAMUSTINE?
A highly interesting and informative subgroup analysis on chemo-
therapy selection arose from the GALLIUM study.
6
The chemo-
therapy choice (bendamustine vs. CHOP vs. CVP) was center
dependent and not the result of a randomization process. As a result,
these data must be interpreted with caution, but several aspects are
noteworthy. The 3‐year PFS rates were highest in the bendamustine
group and lowest in the CVP group. The risk of grade 3–5 adverse
events was higher with CHOP than with CVP or bendamustine, but
most of these events were transient cytopenias. Grade 3–5 infections
were more likely with bendamustine than with CHOP or CVP and
fatal adverse event (AEs) were more common with bendamustine
than with CHOP or CVP. The difference in infections was particularly
notable during the maintenance and follow‐up phase. A potential
explanation is the significant difference in CD4+T‐cell suppression
following treatment. Patients treated with bendamustine experi-
enced profound decreases in CD4+T‐cell counts during bendamus-
tine treatment, with the nadir occurring at end of induction and
failing to recover to baseline even 3 years after treatment, whereas
the T‐cell counts were impacted negligibly by CHOP and CVP ther-
apy. It should be noted that the bendamustine‐treated patients were
slightly older on average than the CHOP‐treated patients, with more
patients over age 70 and 80. However, the age distribution of the
bendamustine and CVP‐treated patient was quite similar. Given the
significant T‐cell depletion experienced after bendamustine‐based
treatment, it is quite possible that maintenance therapy with anti‐
CD20 therapy (and its associate prolonged B‐cell depletion) tips
the risk–benefit ratio unfavorably in FL. Additional data on the risks
versus benefits of maintenance rituximab should come from the Stil
NHL7‐2008 Maintain trial, which prospectively compares 2 versus 4
years of maintenance rituximab following BR induction therapy.
Initial results suggested no major benefit for 4 years over 2 years and
an acceptable safety profile.
7
Attempts to improve the outcomes standard immunochemo-
therapy with the addition of novel agents have been unsuccessful to
date. For example, E2408 was a three‐arm randomized phase II
clinical trial, using BR followed by rituximab maintenance as the
control arm, added the proteasome inhibitor bortezomib to standard
BR induction therapy in one of the experimental arms (BVR with R
maintenance), and added the immunomodulatory agent lenalidomide
to maintenance rituximab in the third arm (BR with lenalidomide,
rituximab (LR) maintenance). The 3‐year PFS was similar in all three
arms, suggesting no benefit for these interventions.
8
6
|
IS SINGLE AGENT RITUXIMAB SUFFICIENT IN
THIS PATIENT POPULATION?
Most of the data examining the role for single agent rituximab in the
frontline management of FL has been generated in patients who
were asymptomatic and had low‐tumor burden by GELF criteria
(see RESORT Trial from Kahl et al., or UK Trial from Ardeshna et al.).
For patients with high‐risk FL, due to high‐tumor burden, there is no
question that single agent rituximab is not as potent as rituximab plus
chemotherapy. Having stated that, there may be situations where it is
reasonable to consider single agent rituximab. Patients may be
elderly and frail, or have significant comorbidities, and the risk of
incorporating chemotherapy may be unacceptably high in certain
circumstances. Or patients may simply refuse treatment with cyto-
toxic chemotherapy for personal reasons. Single agent rituximab can
be adequately efficacious as was demonstrated by Ghielimini et al. in
the SAKK 35/98 trial, where patients were not required to have low‐
tumor burden. The single agent ORR was 67%. Previously untreated
patients receiving a maintenance strategy (n=20) enjoyed a 45%
probability is remaining disease‐free at 5 years, suggesting this
strategy is perfectly reasonable for selected patients. Prior work
from Ghielmini suggests and single agent rituximab loses efficacy
when lymph nodes exceed 5 cm in size and work from Witzig et al.
showed single agent rituximab is quite ineffective in frontline FL if
the lactate dehydrogenase (LDH) is elevated. To summarize, single
agent rituximab can be considered a reasonable option in high‐tumor
burden FL, particularly in elderly or frail patients but clinicians should
be aware that the efficacy appears to be diminished if the tumor
burden is too high or if there is evidence for high proliferation.
7
|
ARE THERE NOVEL STRATEGIES WORTHY OF
FRONTLINE CONSIDERATION?
A novel strategy, combining the immunomodulatory agent lenalido-
mide with rituximab, for the initial management of FL was first re-
ported by investigators from the MD Anderson Cancer Center. The
promising results led to the launch of the RELEVANCE trial.
9
A total
of 1030 patients with previously untreated FL were randomly
assigned to the standard arm of rituximab plus chemotherapy (in-
vestigators choice of R‐CHOP, BR, or R‐CVP) or the experimental
arm of lenalidomide plus rituximab. For the first six cycles, lenalido-
mide was administered orally at 20 mg/day for 3 out of every 4 weeks
of each 28‐day cycle and rituximab was given at 375 mg/m
2
Intra-
venous (IV) on day 1 of each cycle. Patients responding after cycle 6
could continue on therapy for up to 12 more cycles, receiving lena-
lidomide at a dose of 10 mg and rituximab every 8 weeks. The efficacy
between the two strategies was similar in terms of ORR, complete
response rate, PFS and OS. The 3‐year PFS was 77% in the lenali-
domide rituximab arm compared to 78% in the R‐chemotherapy arm.
There was more grade 3–4 neutropenia and febrile neutropenia in the
chemotherapy arms and more rash and cutaneous reactions in the
lenalidomide arm. Despite the excellent results obtained for lenali-
domide–rituximab, it was technically a “negative” study since it was
designed (and failed) to show superiority for the novel combination,
and it has not received a frontline indication in the US or EU. The MD
Anderson group has completed a phase II study of obinutuzumab–
lenalidomide, with promising initial results, exhibiting an ORR of
100% and CR rate of 75% in 57 patients with high‐tumor burden FL.
10
96
-
KAHL
8
|
WHAT ABOUT UNIQUE PATHOBIOLOGIC
SITUATIONS?
There are several potential scenarios that warrant special mention. If
a patients’ biopsy does not demonstrated transformation but the
clinical presentation creates a high level of suspicion for trans-
formation, such as significant B symptoms, hypercalcemia, signifi-
cantly elevated LDH, very high standard uptake values on positron
emission tomography (PET) imaging, is prudent to select
anthracycline‐based immunochemotherapy. If the patients’ diagnostic
biopsy demonstrates grade 3B FL, the preponderance of data sug-
gests these patients are best managed with anthracycline‐based
immunochemotherapy. If the patients’ diagnostic biopsy demon-
strates grade 3A FL, then these patients can be reasonably managed
like typically grade 1–2 FL. Finally, the entity of duodenal FL appears
to have a unique underlying biology and natural history that is more
indolent than typical FL. These patients can often be very successfully
managed with prolonged periods of no active treatment or at most,
single‐agent rituximab, and rarely should chemotherapy be required.
9
|
SUMMARY OF FRONTLINE TREATMENT
CONSIDERATIONS
The last 20 years of research into the management of high‐tumor
burden FL has cemented immunochemotherapy as the standard
approach. However, there is no one universally standard immu-
nochemotherapy regimen. In fact, there is quite a bit of geographic
variation in the standards. The most commonly utilized options
include either obinutuzumab or rituximab combined with either
bendamustine or CHOP chemotherapy. Given the lack of OS benefit
for maintenance therapy with an anti‐CD20, it can be considered
optional. Maintenance anti‐CD20 therapy has a fairly profound
impact on PFS after R‐CHOP, and thus is often utilized. On the other
hand, maintenance anti‐CD20 appears to have much less benefit
after BR therapy, and the GALLIUM study suggests it may do more
harm than good. A summary of outcomes from selected frontline
studies is included in Table 1.
9.1
|
Therapy for relapsed and refractory follicular
lymphoma
Multiple options exist for the treatment of patients who have failed
first‐line therapy, and the decision of which therapy to use depends on
a number of factors, including the prior treatment utilized, duration of
prior response, patient age, comorbid illnesses, and goals of therapy.
Duration of prior responses has consistently been shown to be a
powerful predictor of future outcomes. Patients who experience dis-
ease progression within 24 months (POD24) of frontline immu-
nochemotherapy have been shown to have a 50% overall survival at 5
years, compared with over 90% survival for patients who do not
experience POD24. How to best manage POD24 patients remains
unclear. Retrospective data from stem cell transplant registries have
suggested superior outcomes for transplant strategies in this popu-
lation, and certainly should be considered in young, fit patients. One
word of caution, however, investigators from the British Columbia
Cancer Agency have reported that up to 50% of the POD24 population
TABLE 1Efficacy data in frontline
high‐tumor burden follicular lymphoma Trial NInduction Maintenance 3‐year PFS (%)
PRIMA 513 R‐CHOP/R‐CVP/R‐FCM None 58
505 R‐CHOP/R‐CVP/R‐FCM Rituximab 75
STiL 140 R‐CHOP None 55
139 BR None 75
BRIGHT 186 R‐CHOP/R‐CVP Rituximab in 45% 75
187 BR Rituximab in 43% 80
GALLIUM 341 BR Rituximab 81
345 BO Obinutuzumab 85
203 R‐CHOP Rituximab 77
196 O‐CHOP Obinutuzumab 82
57 R‐CVP Rituximab 77
60 O‐CVP Obinutuzumab 77
E2408 65 BR Rituximab 77
99 BVR Rituximab 82
125 BR R‐lenalidomide 76
RELEVANCE 517 R‐CHOP/BR/R‐CVP Rituximab 78
513 R‐lenalidomide R‐lenalidomide 77
KAHL
-
97
may harbor transformed disease suggesting it is imperative to inves-
tigate this possibility before choosing additional therapy in a POD24
patient.
Besides stem cell transplantation, a variety of nonintensive
strategies exist for R/R FL. Certainly, one can administer repeat
course of immunochemotherapy (e.g., patients relapsing after BR can
receive 0‐CHOP). The increasing menu of novel agents is providing
additional options for management. There are now four PI3 kinase
inhibitors available (idelalisib, duvelisib, copanlisib, and umbrali-
sib).
11–13
Response rates for all three agents tend to run in the 45%–
60% range and average durability is typically around 11 months. The
oral PI3k inhibitors carry the risk of pneumonitis and colitis, although
the risk with umbralisib may be less. Copanlisib does not seem to
have these risks although transient hypertension and hyperglycemia
around administration must be monitored and addressed. More
promising than the PI3k inhibitors is the combination of lenalidomide
and rituximab, as demonstrated in the AUGMENT study.
14
The ORR
for the combination was 78% and the median PFS was 39 months,
compared to 53% and 14 months for rituximab plus placebo. Toxic-
ities were increased compared to the rituximab control arm, most
notably for infection (63% vs. 49%), neutropenia (58% vs. 23%), and
cutaneous reactions (32% vs. 12%). Given the marked improvement
in efficacy, the increased toxicity profile is quite acceptable. Finally, a
first‐in‐class EZH2 inhibitor, tazemetostat, received FDA approval in
R/R FL in the summer of 2020. Activating mutations of EZH2, an
epigenetic regulator, appear to play significant roles in the patho-
genesis of FL. Accordingly, agents designed to suppress EZH2 enzy-
matic activity are being developed. Tazemetostat 15 is an oral EZH2
inhibitor and was tested in 99 patients with R/R FL, 45 of whom
had mutated EZH2 genes and 54 with wild‐type EZH2.
15
In the
EZH2‐mutated patients, the ORR was 69% and the median PFS was
13.8 months. In the EZH2 wild‐type patients, the ORR was 35% and
the median PFS was 11.1 months. The safety profile appears very
good, with negligible grade 3–4 toxicities. The regulatory approval
includes both mutated and wild‐type patient populations. Table 2
summarizes data for the US FDA‐approved targeted agents in R/R FL.
There are several promising investigational immunotherapy ap-
proaches in development in relapsed FL. Targeting the “don't eat me”
CD47 antigen, expressed on many tumor types and preventing
macrophage engulfment, with monoclonal antibodies against CD47
appears promising in early studies. Magrolimab demonstrated an
ORR of 61% and CR rate of 24%, as reported by Advani et al. and the
2019 ICML meeting. The bispecific monoclonocal antibody mosune-
tuzumab targets both CD20 and CD3 and is a potent T‐cell engager.
An ongoing trial has demonstrated an ORR of 68% with an impres-
sive CR rate of 52% in R/R FL. Finally, and perhaps most encouraging,
is recent data generated testing CAR‐T therapy in R/R FL. Axi-
cabtagene ciloleucel (axi‐cel) demonstrated on ORR of 94% with an
CR rate of 80% in a population of R/R FL patients. With a median
follow‐up of 17 months, the 12‐month PFS rate is 77%. More study
and longer follow‐up are needed for these immuno‐oncology agents,
but the early data are very promising and summarized in Table 3.
10
|
SUMMARY
Outcomes are generally very good in FL with median OS exceeding
15 years. As a result, it is sometimes deprioritized as a cancer in need
of therapeutic advances. Certainly, there are FL patients who never
require therapy or who only require one line of therapy and can be
TABLE 2Efficacy data for approved, targeted agents in R/R follicular lymphoma
Agent(s) Class NORR (%) complete response rate (CRR) (%) median progression free survival (mPFS) (m)
Lenalidomide–rituximab Immunomodulatory 147 78 34 39
Rituximab anti‐CD20 MoAb 148 53 18 14
Idelalisib PI3k inhibitor 72 60 15 11
Duvelisib PI3k inhibitor 83 48 2 10
Copanlisib PI3k inhibitor 104 60 14 11
Umbralisib PI3k inhibitor 117 45 5 11
Tazemetostat (mutated) EZH2 inhibitor 45 69 13 14
Tazemetostat (wild‐type) EZH2 inhibitor 54 35 4 11
Abbreviation: ORR, overall response rate.
TABLE 3Investigational
immunotherapy agents with promising
activity in R/R follicular lymphoma
Agent Class NORR (%) CRR (%) Presented
Magrolimab Anti‐CD47 MoAb 41 61 24 Advani, Lugano 2019
Mosunetuzumab Bi‐specific MoAb 62 68 52 Assouline, ASH 2020
Axi‐cel CAR‐T 84 94 80 Jacobson, ASH 2020
Abbreviation: ORR, overall response rate.
98
-
KAHL
considered functional cures. On the other hand, subsets of FL pa-
tients are at high risk of death from their disease. These include
patients with high‐risk m7‐FLIPI scores, patients who experience
recurrence within 2 years of R‐chemotherapy, patients who experi-
ence histologic transformation, and FL patients under the age of 60
at diagnosis. Future research should (a) seek to identify prognostic
biomarkers capable of identifying high‐risk patients at diagnosis; (b)
continue to develop targeted therapies (with predictive biomarkers);
(c) test interventions designed to reduce the risk for histologic
transformation; and (d) seek to reliably cure FL.
CONFLICT OF INTEREST
Dr. Kahl reports consulting fees from Abbvie, Acerta, Celgene,
Genentech, Roche, Pharmacyclics, Gilead, Bayer, AstraZeneca,
Beigene. Dr. Kahl reports research funding from Acerta, Celgene,
Genentech, Beigene.
DATA AVAILABILITY STATEMENT
All data provided in this manuscript is publicly available.
PEER REVIEW
The peer review history for this article is available at https://publons.
com/publon/10.1002/hon.2853.
REFERENCES
1. Marcus R, Davies A, Ando K, et al. Obinutuzumab for the first‐line
treatment of follicular lymphoma. N Engl J Med. 2017;377(14):1331‐
1344. https://doi.org/10.1056/NEJMoa1614598.
2. Federico M, Luminari S, Dondi A, et al. R‐CVP versus R‐CHOP
versus R‐FM for the initial treatment of patients with advanced‐
stage follicular lymphoma: results of the FOLL05 trial conducted
by the Fondazione Italiana Linfomi. J Clin Oncol. 2013;31(12):1506‐
1513. https://doi.org/10.1200/JCO.2012.45.0866.
3. Rummel MJ, Maschmeyer G, Ganser A, et al. Bendamustine plus
rituximab (B‐R) versus CHOP plus rituximab (CHOP‐R) as first‐line
treatment in patients with indolent lymphomas: nine‐year updated
results from the StiL NHL1 study. J Clin Oncol. 2017;35(15_suppl):
7501‐7501. https://doi.org/10.1200/JCO.2017.35.15_suppl.7501.
4. Flinn IW, van der Jagt R, Kahl B, et al. First‐line treatment of pa-
tients with indolent non‐Hodgkin lymphoma or mantle‐cell lym-
phoma with bendamustine plus rituximab versus R‐CHOP or R‐CVP:
results of the BRIGHT 5‐year follow‐up study. J Clin Oncol.
2019;37(12):984‐991. https://doi.org/10.1200/JCO.18.00605.
5. Bachy E, Seymour JF, Feugier P, et al. Sustained progression‐free
survival benefit of rituximab maintenance in patients with follic-
ular lymphoma: long‐term results of the PRIMA study. J Clin Oncol.
2019. JCO.19.01073. https://doi.org/10.1200/jco.19.01073.
6. Hiddemann W, Barbui AM, Canales MA, et al. Immunochemotherapy
with obinutuzumab or rituximab for previously untreated follicular
lymphoma in the GALLIUM study: influence of chemotherapy on
efficacy and safety. J Clin Oncol. 2018;36(23):2395‐2404. https://doi.
org/10.1200/JCO.2017.76.8960.
7. Rummel MJ, Buske C, Hertenstein B, et al. Four versus two
years of rituximab maintenance (R‐maintenance) following bend-
amustine plus rituximab (B‐R): initial results of a prospective,
randomized multicenter phase 3 study in first‐line follicular lym-
phoma (the StiL NHL7‐2008 MAINTAIN study). Blood. 2017;
130(suppl 1):483‐483. https://doi.org/10.1182/blood.V130.Suppl_1.
483.483.
8. Evens AM, Hong F, Habermann TM, et al. A three‐arm randomized
phase II study of bendamustine/rituximab with bortezomib induc-
tion or lenalidomide continuation in untreated follicular lymphoma:
ECOG‐ACRIN E2408. Clin Cancer Res. 2020;26(17):4468‐4477.
https://doi.org/10.1158/1078‐0432.CCR‐20‐1345.
9. Morschhauser F, Fowler NH, Feugier P, et al. Rituximab plus lena-
lidomide in advanced untreated follicular lymphoma. N. Engl J Med.
2018;379(10):934‐947. https://doi.org/10.1056/NEJMoa1805104.
10. Fowler NH, Nastoupil LJ, Chin C, et al. A phase I/II study of lenali-
domide plus obinutuzumab in relapsed indolent lymphoma. Blood.
2019;134(suppl 1):348‐348. https://doi.org/10.1182/blood‐2019‐
131045.
11. Gopal AK, Kahl BS, de Vos S, et al. PI3Kdelta inhibition by idelalisib
in patients with relapsed indolent lymphoma. N Engl J Med.
2014;370(11):1008‐1018. https://doi.org/10.1056/NEJMoa131
4583.
12. Flinn IW, Miller CB, Ardeshna KM, et al. DYNAMO: a phase II study
of duvelisib (IPI‐145) in patients with refractory indolent non‐
Hodgkin lymphoma. J Clin Oncol. 2019;37(11):912‐922. https://doi.
org/10.1200/JCO.18.00915.
13. Dreyling M, Santoro A, Mollica L, et al. Phosphatidylinositol 3‐kinase
inhibition by copanlisib in relapsed or refractory indolent lymphoma.
J Clin Oncol. 2017;35(35):3898‐3905. https://doi.org/10.1200/JCO.
2017.75.4648.
14. Leonard JP, Trneny M, Izutsu K, et al. AUGMENT: a phase III study
of lenalidomide plus rituximab versus placebo plus rituximab in
relapsed or refractory indolent lymphoma. J Clin Oncol.
2019;37(14):1188‐1199. https://doi.org/10.1200/JCO.19.00010.
15. Morschhauser F, Tilly H, Chaidos A, et al. Tazemetostat for pa-
tients with relapsed or refractory follicular lymphoma: an open‐
label, single‐arm, multicentre, phase 2 trial. Lancet Oncol.
2020;21(11):1433‐1442. https://doi.org/10.1016/S1470‐2045(20)
30441‐1.
How to cite this article: Kahl B. High‐risk follicular lymphoma:
Treatment options. Hematological Oncology.
2021;39(S1):94–99. https://doi.org/10.1002/hon.2853
KAHL
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99
Received: 15 February 2021
DOI: 10.1002/hon.2845
SUPPLEMENT ARTICLE
Allogeneic stem cell transplant in non‐Hodgkin lymphomas:
Still an indication?
Peter Dreger
Department of Medicine V, University of
Heidelberg, Heidelberg, Germany
Correspondence
Peter Dreger, Department Medicine V,
University of Heidelberg, Im Neuenheimer
Feld 410, 69120 Heidelberg, Germany.
Email: peter.dreger@med.uni-heidelberg.de
Abstract
Allogeneic hematopoietic cell transplantation (alloHCT) used to play a defined role in
the treatment of non‐Hodgkin lymphoma (NHL). With the advent of modern targeted
molecular therapies and immunotherapies, treatment standards at least for B‐cell
lymphoma have undergone significant changes, thereby questioning the traditional
role of alloHCT in these diseases. This paper attempts to describe the current place
and the perspectives of alloHCT in the rapidly evolving treatment landscape of NHL.
KEYWORDS
allogeneic transplantation, CAR‐T cells, lymphoma, NHL
1
|
INTRODUCTION
Entering the clinical stage more than 50 years ago, allogeneic he-
matopoietic cell transplantation (alloHCT) was the first immuno-
therapy successfully applied to patients, and can be considered as the
ancestor of modern cellular immunotherapy.
1
Despite its inherent
drawbacks of significant non‐relapse mortality and morbidity due to
graft‐versus‐host disease, until recently, alloHCT has been playing a
defined role in the management algorithms of the main NHL subtypes
(i.e., diffuse large B‐cell lymphoma [DLBCL]; follicular lymphoma [FL];
mantle cell lymphoma [MCL]; and peripheral T‐cell lymphoma
[PTCL]), mostly in the salvage setting. With the advent of modern
targeted molecular therapies and immunotherapies, treatment stan-
dards at least for B‐cell lymphoma have undergone substantial
changes, thereby questioning the traditional role of alloHCT in these
diseases. This paper attempts to describe the current place and the
perspectives of alloHCT in the rapidly evolving treatment landscapes
of DLBCL, FL, MCL, and PTCL.
2
|
DIFFUSE LARGE B‐CELL LYMPHOMA
As in almost all neoplastic indications where it is effective, the basis
of alloHCT in DLBCL is graft‐versus‐lymphoma activity (GVL).
Circumstantial evidence for GVL efficacy in DLBCL can be derived
from the effectiveness of immunomodulation for preventing or
treating post‐transplant relapse, and from observations showing that
non‐myeloablative alloHCT can provide long‐term disease control in
patients having failed autologous hematopoietic cell transplantation
(autoHCT). However, compared to the other main NHL entities,
DLBCL appears to be less GVL‐sensitive resulting in long‐term
progression‐free survival rates of 30%–40%, and even less if calcu-
lated by intent‐to‐treat.
2–4
While the standard indication for alloHCT in DLBCL used to
be chemosensitive disease following failure of autoHCT, chimeric
antigen receptor‐engineered T‐cells (CARTs) have become the
preferred cellular immunotherapy in this setting.
3
A preliminary
intent‐to‐treat comparison of alloHCT versus CARTs in large B‐cell
lymphoma (LBCL) suggested that in patients having failed at least
two lines of systemic therapy, survival tended to be better with
the CART versus the alloHCT approach.
5
One limitation of this
study was the short follow‐up of 10 months in the CART group.
Figure 1shows an update of this comparison with a median
follow‐up of 15 (9–24) months, suggesting that the favorable trend
for CARTs was maintained, both measured from treatment indi-
cation and start of cellular therapy.
In conclusion, for the time being, alloHCT remains an indication
for advanced DLBCL when CARTs have failed or are not feasible.
3
This is an open access article under the terms of the Creative Commons Attribution‐NonCommercial License, which permits use, distribution and reproduction in any
medium, provided the original work is properly cited and is not used for commercial purposes.
© 2021 The Authors. Hematological Oncology published by John Wiley & Sons Ltd.
100
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Hematological Oncology. 2021;39(S1):100–103. wileyonlinelibrary.com/journal/hon
However, it is clear that emerging innovations, such as bispecific
antibodies and moving CARTs to the second line, have the potential
for further modifying the importance of alloHCT for rescuing patients
with relapsed/refractory DLBCL.
3
|
FOLLICULAR LYMPHOMA
Although FL appears to be the most GVL‐sensitive disease among all
alloHCT indications currently considered as standard, with a 5‐year
relapse risk less than 20% in all major studies published,
2,6
the
number of allogeneic transplantations for this subtype is decreasing
since several years, making FL the least frequent allo indication of the
four entities discussed in this review. In 2018, the numbers of allo-
transplants registered with the European Society for Blood and
Marrow Transplantation (EBMT) for PTCL, DLBCL, MCL, and FL were
401, 320, 161, and 144, respectively (EBMT data on file, PROMISE
download 19 February 2020). This has to do with the indolent course
of the disease, the high efficacy of standard first‐line treatment with
chemoimmunotherapies and CD20 antibody maintenance, and the
availability of a broad effective toolkit for salvage treatment,
including revlimid, targeted therapies, and also autoHCT. Even in
high‐risk disease, defined by failure of first‐line treatment within
2 years (“POD24”), there is no proven benefit of alloHCT over
autoHCT.
7
In contrast to DLBCL and MCL, there is no CART therapy
approved for FL available to date, and due to the indolent character
of the disease the benefit of CART approaches in terms of durable
lymphoma control will be more difficult to assess. Nevertheless, the
development of CD19‐directed CARTs and other immunotherapies
for indolent lymphoma is already quite advanced, suggesting that the
alloHCT indication will further narrow in the near future.
For today, alloHCT is still a potentially curative option for those
patients with FL who are resistant to less aggressive approaches, that
is, who relapse early after salvage autoHCT or a similarly intensive
regimen, and for patients with emerging exhaustion of hematopoie-
sis, or incipient myelodysplasia.
4
|
MANTLE CELL LYMPHOMA
Efficacy of donor lymphocyte infusions (DLI) and plateaus in the
relapse curves after reduced intensity conditioning (RIC) suggest that
there is a biologically relevant contribution of GVL also in MCL.
8,9
Given the poor prognosis of MCL recurring after state‐of‐the‐art
intensive first‐line treatment with consolidating autoHCT and ritux-
imab maintenance, the traditional place of (RIC) alloHCT has been
consolidation of second‐line responses. With the introduction of
Bruton's tyrosine kinase inhibitors (BTKi) as standard of care salvage
therapy in MCL, and the recent approval of the CART product
brexucabtagene autoleucel for relapsed/refractory MCL, the place of
alloHCT in the MCL management algorithm needs to be re‐evaluated.
A recent international consensus project recommended considering
alloHCT in MCL only if CARTs have failed or are not feasible
(Hamadani et al., manuscript in preparation). This would mean that
alloHCT comes into play only on the fourth place after standard in-
duction, BTKi, and CARTs. However, in areas where CARTs are not
available, considering alloHCT already for consolidation of second‐
line responses to BTKi might be worthwhile in high‐risk patients,
such as those without a complete response to BTKi or early failure
after standard induction.
10
Again, the expected advent of novel
molecular agents and immunotherapeutics in the clinical routine of
MCL management, such as venetoclax, enhanced CD19‐directed
antibodies, and next‐generation phosphatidylinositol 3‐kinase delta
inhibitors has the potential to further differentiate the alloHCT
indication in MCL in the near future.
5
|
PERIPHERAL T‐CELL LYMPHOMA
In contrast to B‐cell lymphoma, there have been no major therapeutic
improvements for PTCL in the last decades, with the exception of
anaplastic large cell lymphoma (ALCL). Although the value of autoHCT
consolidation is ambiguous, accepted standard treatment for the three
predominant nodal PTCL subsets (i.e., ALK‐negative ALCL, PTCL not
other specified [PTCL‐NOS], and angioimmunoblastic T‐cell lymphoma
FIGURE 1 Overall survival of patients with diffuse large B‐cell lymphoma beyond the second line by cellular immunotherapy intended
(Heidelberg, 2005–2020, N=80). (A) Survival from indication; (B) Survival from administration of cellular immunotherapy. CAR, chimeric
antigen receptor T‐cells; HCT, allogeneic hematopoietic cell transplantation; HCT>2L, HCT intended after having failed two or more lines
DREGER
-
101
[AITL]) consists in CHOP‐like induction followed by high‐dose inten-
sification.
11
With this strategy, 5‐years progression‐free survival rates
of 35%–45% can be expected.
12
Of particular concern in PTCL is the
high rate of primary refractoriness which can affect up to one third of
the patients.
Similar to FL and MCL, PTCL appears to be quite susceptible to
GVL effects as illustrated by survival plateaus around 50% after
alloHCT across numerous studies and efficacy of DLI,
2,4,8,12,13
prompting the exploration of allotransplantation as first‐line
consolidation. A large randomized trial comparing alloHCT with
autoHCT in the first‐line setting, however, failed to show a benefit for
the alloHCT strategy, largely because the lower relapse risk associ-
ated with alloHCT was neutralized by excess non‐relapse mortality.
14
Thus, except for selected orphan PTCL subsets such as hepatosplenic
T‐cell lymphoma, first‐line alloHCT should not be performed outside
of clinical trials.
In contrast, alloHCT is the preferred option in relapsed/re-
fractory PTCL, ideally after having achieved a state of controlled
disease prior to transplant.
11,12
This is because of the lack of thera-
peutic alternatives with curative perspective. In patients not having
undergone autoHCT during first‐line treatment, also auto-
transplantation may be considered though appearing inferior to
alloHCT in intent‐to‐treat comparisons.
13
Similar to the other lym-
phoma subsets described in this paper, reduced intensity condition-
ing provides outcomes in PTCL that are at least similar to that
observed after myeloablative conditioning, and haplo‐identical do-
nors seem to be a valuable alternative if matched related or unre-
lated donors are not available.
12
6
|
CONCLUSIONS
Although substantial therapeutic innovations in particular for B‐cell
lymphoma have entered the clinical stage recently, or are at the
doorstep, immunotherapy by alloHCT remains an effective and
potentially curative option for settings where the medical need un-
met by traditional chemotherapy can also not be covered by novel
therapeutics. This gap might be bigger than believed as some
promises of novel agents given in phase‐2 studies have not been fully
kept in the real world.
15
Suggestions for current indications for
alloHCT are summarized in Table 1. If alloHCT is taken into account
according to these suggestions, it has to be kept in mind that the
window of opportunity for a successful outcome of transplantation is
largest before tumor refractoriness and performance status deteri-
oration have developed through serial palliative or experimental
treatment attempts.
ACKNOWLEDGMENT
I thank Herve Finel for providing the EBMT registry data used here.
CONFLICT OF INTEREST
P. Dreger: consultancy for AbbVie, AstraZeneca, Gilead, Janssen,
Novartis, Riemser, Roche; speakers bureau for AbbVie, AstraZeneca,
Gilead, Novartis, Riemser, Roche; research support from Riemser.
REFERENCES
1. Mathe G, Amiel JL, Schwarzenberg L, et al. Successful allogeneic bone
marrow transplantation in man: chimerism, induced specific toler-
ance, and possible anti‐leukemic effects. Blood. 1965;25(2):179‐196.
2. Urbano‐Ispizua A, Pavletic SZ, Flowers ME, et al. The impact of
graft‐versus‐host disease on the relapse rate in patients with
lymphoma depends on the histological subtype and the intensity
of the conditioning regimen. Biol Blood Marrow Transpl. 2015;
21(10):1746‐1753.
3. Dreger P, Fenske TS, Montoto S, Pasquini MC, Sureda A, Hamadani
M. Cellular immunotherapy for refractory diffuse large B cell lym-
phoma in the chimeric antigen receptor‐engineered T cell era: still a
role for allogeneic transplantation? Biol Blood Marrow Transpl.
2020;26(4):e77‐e85.
4. Selberg L, Stadtherr P, Dietrich S, et al. The impact of allogeneic
hematopoietic cell transplantation on the mortality of poor‐risk non‐
Hodgkin lymphoma: an intent‐to‐transplant analysis. Bone Marrow
Transpl. 2021;56(1):30‐37.
5. Dreger P, Dietrich S, Schubert M‐L, et al. CAR T cells or allogeneic
transplantation as standard of care for advanced large B‐cell lymphoma:
an intent‐to‐treat comparison. Blood Adv. 2020;4(24):6157‐6168.
6. Sureda A, Zhang M‐J, Dreger P, et al. Allogeneic hematopoietic
stem cell transplantation for relapsed follicular lymphoma: a
combined analysis on behalf of the Lymphoma Working Party of
the EBMT and the Lymphoma Committee of the CIBMTR. Cancer.
2018;124(8):1733‐1742.
7. Smith SM, Godfrey J, Ahn KW, et al. Autologous transplantation versus
allogeneic transplantation in patients with follicular lymphoma expe-
riencing early treatment failure. Cancer. 2018;124(12):2541‐2551.
8. Robinson S, Boumendil A, Finel H, et al. Donor lymphocyte infusions
induce durable responses in patients with follicualr, mantle and T
cell lymphomas relapsing after an alloSCT. An EBMT‐LWP study.
Hematol Oncol. 2020;37(Suppl 2):316‐317. Ref Type: Abstract.
TABLE 1Select lymphoma alloHCT
standard indications at a glance
�Large B‐cell lymphoma: 4
th
line after failure of induction, autoHCT attempt, and CAR T‐cell
therapy.
�Follicular lymphoma: early relapse after salvage autoHCT or a similarly intensive regimen, and
emerging exhaustion of hematopoiesis/incipient myelodysplasia.
�Mantle cell lymphoma: 4
th
line after failure of induction, BTKi, and CAR T‐cell therapy.
�Peripheral T‐cell lymphoma: relapsed/refractory disease.
Abbreviations: alloHCT, allogeneic hematopoietic cell transplantation; autoHCT, autologous
hematopoietic cell transplantation; BTKi, Bruton's tyrosine kinase inhibitors; CAR T‐cell therapy,
chimeric antigen receptor‐engineered T‐cell therapy.
102
-
DREGER
9. Robinson SP, Boumendil A, Finel H, et al. Long‐term outcome anal-
ysis of reduced‐intensity allogeneic stem cell transplantation in
patients with mantle cell lymphoma: a retrospective study from
the EBMT Lymphoma Working Party. Bone Marrow Transpl.
2018;53(5):617‐624.
10. Visco C, Tisi MC, Evangelista A, et al. Time to progression
of mantle cell lymphoma after high‐dose cytarabine‐based
regimens defines patients risk for death. Br J Haematol. 2019;
185(5):940‐944.
11. d'Amore F, Gaulard P, Trümper L, et al. Peripheral T‐cell lymphomas:
ESMO clinical practice guidelines for diagnosis, treatment and
follow‐up. Ann Oncol. 2015;26(Suppl 5):v108‐v115.
12. Schmitz N, Lenz G, Stelljes M. Allogeneic hematopoietic stem
cell transplantation for T‐cell lymphomas. Blood. 2018;132(3):
245‐253.
13. Chihara D, Fanale MA, Miranda RN, et al. The survival outcome of
patients with relapsed/refractory peripheral T‐cell lymphoma‐not
otherwise specified and angioimmunoblastic T‐cell lymphoma. Br J
Haematol. 2017;176(5):750‐758.
14. Schmitz N, Truemper L, Bouabdallah K, et al. A randomized phase 3
trial of auto vs. allo transplantation as part of first‐line therapy in
poor‐risk peripheral T‐NHL. Blood. 2020:137. https://doi.org/10.
1182/blood.2020008825
15. Pasquini MC, Hu Z‐H, Curran K, et al. Real‐world evidence of tisa-
genlecleucel for pediatric acute lymphoblastic leukemia and non‐
Hodgkin lymphoma. Blood Adv. 2020;4(21):5414‐5424.
How to cite this article: Dreger P. Allogeneic stem cell
transplant in non‐Hodgkin lymphomas: Still an indication?
Hematological Oncology. 2021;39(S1):100–103. https://doi.
org/10.1002/hon.2845
DREGER
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Received: 17 February 2021
DOI: 10.1002/hon.2844
SUPPLEMENT ARTICLE
Optimizing CAR T cell therapy in lymphoma
David Qualls |Gilles Salles
Lymphoma Service, Department of Medicine,
Memorial Sloan Kettering Cancer Center, New
York, New York, USA
Correspondence
Gilles Salles, Lymphoma Service, Department
of Medicine, Memorial Sloan Kettering Cancer
Center, New York, New York, USA.
Email: sallesg@mskcc.org
Abstract
Chimeric antigen receptor (CAR) T cell therapy has significantly improved the
outlook for patients with certain types of poor‐risk lymphoma. Despite these ad-
vances, a majority of patients undergoing CAR T therapy will suffer progression or
relapse of disease, and toxicity remains a concern. Additionally, the patients and
disease subtypes that are most likely to benefit from CAR T have yet to be fully
defined. Many ongoing trials are exploring novel CAR T approaches to address these
concerns. In this review, we highlight some of the primary strategies and relevant
studies aimed at improving the utility of CAR T therapy in lymphoma.
KEYWORDS
cellular therapy, chimeric antigen receptor T cell, lymphoma
1
|
INTRODUCTION
In 2017, the first chimeric antigen receptor (CAR) T cell therapy was
approved for use in relapsed or refractory aggressive B cell lym-
phoma. The initial CAR T studies demonstrated remarkable efficacy
in a population of patients with otherwise dismal outcomes. In the
4 years since, there has been a marked expansion in the use of CAR T
cell therapy and the development of novel CAR T strategies for the
management of lymphoma.
Despite these encouraging results, significant challenges and
opportunities for improvement in CAR T therapy remain. While the
majority of patients attain responses to treatment, most patients will
eventually develop relapsed or refractory disease. Toxicity also
remains a major limitation to CAR T therapy; cytokine release
syndrome (CRS) and immune effector cell‐associated neurotoxicity
syndrome (ICANS) often require hospitalization and present a major
source of cost and morbidity.
With the goal of addressing these shortcomings, over 200 clinical
trials investigating CAR T therapy in lymphoma are underway, with
more strategies in preclinical development (clinicaltrials.gov). This
review aims to highlight some of the most promising strategies for
improving the outcomes of lymphoma patients using CAR T therapy.
Some of the greatest opportunities for advancement include broad-
ening the eligible patient pool and identifying those most likely to
benefit from CAR T, expediting CAR T manufacturing, optimizing
lymphodepletion, improving CAR T design, and co‐administering
agents that may improve the efficacy or reduce the toxicity of CAR T
therapy.
2
|
CURRENT PRACTICE
At time of writing, three products, axicabtagene ciloleucel (axi‐cel),
tisagenlecleucel (tisa‐cel), and most recently, lisocabtagene mar-
aleucel (liso‐cel), are available for commercial use in relapsed or
refractory large B cell lymphoma in various countries. Results with
each agent in their index clinical trials are summarized in Table 1.
Encouraging overall response rates ranging from 52%–82% were
reported, with 12‐month overall survival of 48%‐59%.
1–3
These re-
sults compared favorably with historical outcomes in relapsed or
refractory DLBCL, where patients undergoing conventional salvage
therapy had a median overall survival of 6.3 months.
4
All three agents
had characteristic toxicity profiles, with severe (grade ≥3) CRS in
1%–22% of patients, and severe (grade ≥3) neurotoxicity in 12%–
28% of patients. Similar efficacy and toxicity outcomes have been
noted in real‐world analyses where patients were, on average, older
and with more comorbidities. Trial design and outcomes are reviewed
in greater detail in Table 1, and more detailed analysis of these three
products have recently been published.
5
Most recently, brexucabtagene autoleucel (brexu‐cel) demon-
strated promising results in relapsed or refractory mantle cell
lymphoma (MCL) and is now commercially available.
6
In the ZUMA‐2
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Hematological Oncology. 2021;39(S1):104–112. wileyonlinelibrary.com/journal/hon © 2021 John Wiley & Sons Ltd.
trial, brexu‐cel demonstrated an overall response rate (ORR) of 93%,
and prolonged 12‐month progression‐free and overall survival at
61% and 83%, respectively. Most patients had CRS and neurotoxicity,
with 15% developing grade 3 CRS and 31% having grade ≥3 ICANS.
3
|
PATIENT SELECTION
At time of publication, there are no reliable predictive models to
anticipate treatment efficacy or toxicity in CAR T recipients, and this
remains an active area of investigation. The only readily reproducible
determinant to date associated with response is the degree of tumor
burden, as reflected by tumor volume or lactate dehydrogenase
(LDH). Other data suggest that patients with an altered performance
status (Eastern Cooperative Oncology Group (ECOG) >1) or a
heightened inflammatory state (C‐reactive protein elevation) have a
higher risk of treatment failure.
7,8
Factors classically associated with
prognosis with standard chemoimmunotherapy, such as age, prior
therapy, International Prognostic Index (IPI), and cell of origin, are
not predictive of outcome in CAR T therapy. Other tumor
biomarkers, including immune checkpoint molecules such as PD‐L1
status, LAG‐3 expression, and TIM‐3 have been investigated with
conflicting results in their predictive capacity.
9
A major determinant of response may be the quality and
composition of the patient's autologous T cells that are engineered
into CAR T cells. In one study of chronic lymphocytic leukemia (CLL)
patients, sustained remission was seen in patients with higher
proportions of a T cell subset with CD45RO
−
CD27
+
CD8
+
immuno-
phenotype, characterized by long‐lived memory cells in a resting
state, with high capacity for expansion and acquisition of effector
functions on antigen re‐exposure.
10
CD27
+
PD‐1
−
CD8
+
cells with
high expression of IL‐6R were also predictive of response, providing
potentially intriguing rationale for the interruption of the PD‐1/PD‐
L1 axis via CAR T modification or concomitant checkpoint blockade.
T cell polyfunctionality, defined as the capacity of a T cell subset to
deploy multiple immune programs, has also been associated with
both increased overall response and toxicities.
11
These factors may
not only provide prognostic guidance, but also help refine our prac-
tices in preservation and collection of an adequate T cell product. T
cell fitness is compromised by chemotherapy, particularly regimens
incorporating bendamustine, and avoiding such regimens or collect-
ing prior to such treatments may allow for more effective CAR T
products.
12
4
|
EXPANDING CAR T INDICATIONS
Commercially available CAR T products are approved for use in
relapsed or refractory diffuse large B cell lymphoma, high‐grade large
B cell lymphoma, transformed follicular lymphoma, and MCL. Intui-
tively these constructs, all targeting the CD19 cell surface antigen,
are likely to have efficacy in other B cell lymphomas, and ongoing
TABLE 1Landmark clinical trials in CAR T cell therapy for lymphoma
ZUMA‐1 JULIET TRANSCEND ZUMA‐2
CAR T cell
product
Axicabtagene ciloleucel
(axi‐cel, Yescarta)
Tisagenlecleucel (tisa‐cel,
Kimriyah)
Lisocabtagene maraleucel (liso‐cel,
JCAR017)
Brexucabtagene autoleucel (brexu‐cel,
Tecartus)
Bridging therapy None 93% 72% 37%
Lymphodepletion Flu/Cy 500/30 �3d Flu/Cy 250/25 �3d versus
Benda
Flu/Cy 300/30 �3d Flu/Cy 500/30 �3d
Construct Anti‐CD19 scFV, CD28,
CD3ζ
Anti‐CD19 scFV, 4‐1BB,
CD3ζ
Anti‐CD19 scFV, 4‐1BB, CD3ζAnti‐CD19 scFV, CD28, CD3ζ
Disease
indications
DLBCL, HGBCL, tFL,
PMBCL
DLBCL, HGBCL, tFL DLBCL, HGBCL, tFL, PMBCL, FL
grade 3B
MCL
Prior lines of
therapy
≥2≥2≥2≥2 (prior anti‐CD20, anthracycline,
BTKi required)
ORR 82% 52% 80% 93%
12 month PFS 44% (34–53) N/A 44.1% (37.3–50.7) 61%
12 month OS 59% (49–68) 48.2% (38.6–57.1) 57.9% (51.3–63.8) 83%
CRS (Grade ≥3) 93% (13%) 58% (22%) 35% (1%) 91% (15%)
ICANS (Grade
≥3)
64% (28%) 21% (12%) 19% (13%) 63% (31%)
Note: These studies have resulted in regulatory approval and commercial availability of their respective CAR T products.
Abbreviations: Benda, bendamustine; BTKi, bruton tyrosine kinase inhibitor; CAR, chimeric antigen receptor; CRS, cytokine release syndrome; d, days;
DLBCL, diffuse large B‐cell lymphoma; Flu/Cy, fludarabine/cyclophosphamide; HGBCL, high grade B‐cell lymphoma; ICANS, immune effector cell‐
associated neurotoxicity syndrome; MCL, mantle cell lymphoma; N/A, not available; ORR, overall response rate; OS, overall survival; PFS, progression‐
free survival; PMBCL, primary mediastinal B‐cell lymphoma; scFV, single chain variable fragment; tFL, transformed follicular lymphoma.
QUALLS AND SALLES
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105
studies have demonstrated encouraging preliminary results in other
subtypes, including indolent diseases such as follicular lymphoma,
marginal zone lymphoma, and chronic lymphocytic leukemia.
While indolent lymphomas can often be observed or controlled
with first‐line therapies, many patients will ultimately develop
multiply relapsed disease refractory to currently available treat-
ments. Preliminary data (Table 2) from ongoing Phase 2 studies
evaluating axi‐cel, tisa‐cel, and liso‐cel have demonstrated promising
efficacy, though final results and Food and Drug Administration
(FDA) review are pending.
13–16
Outside the realm of B‐cell non‐Hodgkin lymphoma, CAR T cell
therapy is being explored in Hodgkin lymphoma and T cell lymphoma.
An anti‐CD30 CAR T cell therapy was recently developed with
encouraging preliminary data for Hodgkin lymphoma.
17
While T cell
lymphoma is an intriguing target for CAR T therapy, there are a
number of unique challenges to this approach. While patients can
tolerate the sustained B‐cell aplasia associated with anti‐CD19
therapy, a similar elimination of the T cell pool would likely cause
severe immunosuppression and lead to infectious complications. As
such, CAR T cells must target cell surface antigens that are dispro-
portionately expressed on the T cell malignancy as compared to the
normal T cell repertoire in order to mitigate “on‐target, off‐tumor”
toxicity. Targets of interest at this time include CD5, CD7, TRBC1,
CD37, CD38, and B7‐H3, among others. Another challenge is
CAR T cell fratricide—the possibility of CAR T cells recognizing a
self‐antigen, triggering cytotoxic killing of other CAR T cells. One
potential solution is to alter expression of the target antigen on the
CAR T cells themselves.
Alongside histologic indications, the use of CAR T therapy in CNS
lymphoma is gradually expanding. The initial landmark trials for axi‐
cel and tisa‐cel excluded patients with active CNS disease, given
unclear efficacy and potential for neurotoxicity. Since then, small
studies had shown that commercial CAR T therapy off trial demon-
strated efficacy in secondary CNS lymphoma with no evidence of
excess neurotoxicity.
18,19
The TRANSCEND phase II study of liso‐cel
included seven patients (3%) with secondary CNS lymphoma, with
three of six evaluable patients achieving complete response.
3
Studies
incorporating patients with primary CNS lymphoma are also
underway.
5
|
INCLUDING CAR T IN EARLIER LINES OF
THERAPY
The commercial use of CAR T therapy is currently approved in the
setting of multiply relapsed/refractory disease. Patients with
aggressive lymphomas who have failed two prior lines of chemo-
immunotherapy are more likely to have complications from their
disease or prior treatment; as a result, they may have more extensive
disease or greater comorbidities at the time of CAR T therapy.
Understandably, there is interest in determining whether CAR T
therapy in an earlier phase of treatment is appropriate. Three
ongoing Phase 3 clinical trials are investigating the three main CAR T
products in the second line setting. In these studies, patients with
relapsed or refractory DLBCL after first‐line chemoimmunotherapy
that are transplant eligible are randomized to receive either up‐front
CAR T cell therapy or the current standard of care, salvage chemo-
immunotherapy followed by autologous stem cell transplantation.
20
Axi‐cel CAR T therapy is also being investigated in the first‐line
setting for those with aggressive B cell lymphoma with initial
adverse characteristics in ZUMA‐12.
21
In this Phase 2 study, pa-
tients with positive interim PET after two cycles chemo-
immunotherapy underwent leukapheresis followed by
lymphodepletion and CAR T therapy. Interim analysis of 32 patients
revealed an ORR of 85% and CR rate of 74%, which compares
favorably with historical controls.
21
6
|
EXPEDITING THE COLLECTION,
MODIFICATION AND EXPANSION OF CAR T CELL
THERAPY
A significant challenge to the implementation of CAR T therapy is the
delay required for collection, modification, and expansion of CAR T
cells. Median turnaround time from apheresis to infusion in a real‐
world analysis of commercial therapy was 28 days for axi‐cel and
44 days for tisa‐cel in the United States.
22
Fourteen (9%) of patients
receiving axi‐cel and 3 (4%) of those receiving tisa‐cel died from
progression of disease prior to infusion.
Point‐of‐care CAR T manufacturing, as opposed to the current
model of centralized CAR T manufacturing, has already shown
promise. A closed‐system manufacturing platform capable of T cell
enrichment, CAR vector transduction, washing and expansion at the
treatment site has already been utilized in phase I clinical trials, with
successful production of effective CAR T cells and turnaround time
from apheresis to infusion of 14 days
23,24
Such systems would allow
for more rapid administration of CAR T product to patients and may
prove more cost‐effective over time.
Another approach is the use of an allogeneic CAR T product
derived from healthy donors, which would bypass the delays and
costs of autologous CAR T cell collection and manufacturing alto-
gether, while also avoiding the use of potentially dysfunctional
patient‐derived T cells. Challenges to such an approach include the
risk of graft versus host disease (GVHD) and host rejection of the
allogeneic CAR T cell. The ALPHA study is an ongoing phase I trial
investigating ALLO‐501, an allogeneic anti‐CD19 CAR T product.
25
ALLO‐501 is genetically modified to disrupt the TCR alpha con-
stant gene as prevention against GVHD. CD52 is also disrupted to
allow administration of an anti‐CD52 monoclonal antibody for
host‐specific lymphodepletion, with the goal of preventing CAR T
rejection. Preliminary results of the first nine evaluable patients
showed encouraging initial response rates with ORR 78%, though
three of seven responders subsequently progressed. While dura-
bility of response remains a question, response rates are encour-
aging and such products may be useful as a bridge to other
therapies, such as allogeneic stem cell transplantation. Alongside
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QUALLS AND SALLES
allogeneic CAR T cells, CAR‐modified allogeneic natural killer (NK)
cells represent a promising novel therapy, and have shown activity
in non‐hodgkin lymphoma (NHL).
26
Potential advantages include
the ability to administer HLA‐mismatched products, and avoidance
of the CRS and neurotoxicity seen in CAR T therapy, though
questions remain about NK cell persistence and long‐term disease
control (Table 3).
7
|
OPTIMIZING LYMPHODEPLETION
Lymphodepletion prior to CAR T infusion has been associated with
improved CAR T cell expansion and antitumor efficacy in hematologic
malignancies.
27
It is thought that lymphodepletion benefits CAR T
cell function via several mechanisms, including the clearance of
endogenous lymphocytes that act as “cytokine sinks” and improved
access to cytokines that facilitate T cell expansion, removal of
immunosuppressive cells such as regulatory T cells and myeloid‐
derived suppressor cells, and improved function of antigen‐
presenting cells.
28
While lymphodepletion incorporating fludarabine
and cyclophosphamide (Flu/Cy) is an established component of
CAR T therapy, there is little head‐to‐head data to guide the choice
of agents or dosing.
The role of lymphodepletion in modulating the host immune
profile is gaining increasing interest. In one study, an increase in
monocyte chemoattractant protein‐1 after lymphodepletion, and
higher interleukin‐7 (IL‐7) peak, were associated with improved
progression‐free survival (PFS) in CAR T recipients. Higher‐intensity
Flu/Cy conditioning was associated with this favorable cytokine
profile, suggesting that modification of the lymphodepletion regimen
to achieve an optimal cytokine response may result in better out-
comes.
29
Another recent preclinical study investigating CAR T ther-
apy in models of lung cancer found that including oxaliplatin in the
lymphodepletion regimen increased intratumor macrophage pro-
duction of T‐cell recruiting cytokines and improved CAR T cell tumor
infiltration.
30
Whether a similar strategy of employing immunogenic
chemotherapy would be efficacious in B cell malignancies remains to
be seen.
8
|
BUILDING A BETTER CAR
8.1
|
Improving CAR design
CAR T cells are produced by the transduction, via lentivirus or
retrovirus, of a genetically engineered CAR into an autologous T cell
population. All commercially available products utilize a “second‐
generation” CAR, which consists of an extracellular antigen‐binding
single chain variant domain (scFV), which targets the B cell antigen
CD19; hinge and transmembrane domains, often derived from CD8α
or an extension of CD28; a CD3‐derived activation domain; and one
or more costimulatory domains, most commonly either CD28 or
4‐1BB. Many variations on this CAR T product are being explored in
preclinical and early clinical trials, exploring modifications in the
number and type of costimulatory domains, the use of alternative
targets or dual‐targeted CAR products.
TABLE 2Selected clinical trials investigating expanded indications for CAR T therapies, including indolent lymphoma, CLL, and MCL
ZUMA‐5 TRANSCEND NHL 001 (MCL) TRANSCEND CLL 004 ELARA
Disease indications FL grade 1‐3A, EN MZL MCL CLL FL grade 1‐3A
Prior lines of therapy ≥2 (anti‐CD20, alkylating
agent required)
≥2 (anti‐CD20, alkylating
agent, BTKi required)
≥3 (standard‐risk disease) ≥2
(high‐risk disease)
≥2 (anti‐CD20, alkylating
agent required)
CAR T cell product Axi‐cel Liso‐cel Liso‐cel Tisa‐cel
Median follow‐up,
months
17.5 10.9 (DL1), 3.1 (DL2) 18 6.5
Patients enrolled (treated
per protocol)
151 (151) 42 (32) 23 (22) 98 (52)
CRR (95% CI) 76% 59% 45% 71.1% (56.5–84.0)
ORR (95% CI) 92% (85–97) 84% 82% 84.8% (71.1–93.7)
% Patients with ongoing
response
72% at 12 months ‐50% at 18 months 84.4% at 6 months
CRS (Grade ≥3) 82% (7%) 50% (3%) N/A (9%) 48% (0%)
ICANS (Grade ≥3) 60% (19%) 28% (9%) N/A (22%) 10% (2%)
Note: Of note, outcomes of TRANSCEND NHL 001, TRANSCEND CLL 004, and ELARA are preliminary and based on the most recent available published
results at time of writing.
Abbreviations: BTKi, Bruton tyrosine kinase inhibitor; CAR, chimeric antigen receptor; CLL, chronic lymphocytic leukemia; CRR, complete response rate;
CRS, cytokine release syndrome; DL, dose level; DOR, duration of response; EN MZL, extranodal marginal zone lymphoma; FL, follicular lymphoma;
ICANS, immune effector cell‐associated neurotoxicity; ITT, intention to treat; NHL, non‐hodgkin lymphoma; ORR, overall response rate; PP, per
protocol.
QUALLS AND SALLES
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8.2
|
Fine‐tuning CAR signaling
After binding target antigen, intracellular domains trigger down-
stream signals leading to T cell activation, proliferation, and anti-
tumor cytotoxicity. The degree of downstream activation appears
to be crucial in determining efficacy. Inadequate signaling leads to
insufficient antitumor activity and poor T cell persistence, whereas
excessive or redundant T cell activation can drive CAR T
exhaustion. Several strategies to optimize CAR signaling are un-
derway investigating various components of the CAR construct
(Figure 1).
So‐called “third‐generation” CARs have been developed which
carry both CD28 and 4‐1BB costimulatory domains, with unclear
benefit to date. In one Phase 1 trial of patients with NHL, patients
were simultaneously infused with both second‐and third‐generation
CAR T cells, with the later CAR T cells exhibited greater expansion
and persistence than second generation CAR T cells, particularly in
patients with lower disease burden.
31
Reducing the activation potential may also improve CAR T cell
persistence and limit exhaustion, allowing for more durable
responses. Modification of the CD3ζactivation domain in order to
modulate the activation potential of CARs has yielded intriguing
TABLE 3Challenges and strategies for improvement of CAR T therapy for lymphoma
Challenge Strategies for improvement Examples
Prolonged time to treatment Point‐of‐care CAR T manufacturing Closed‐system platforms
Off‐the‐shelf allogeneic CAR T product ALLO‐501
Autologous T cell
dysfunction
Off‐the‐shelf allogeneic CAR T product ALLO‐501
Avoiding lymphotoxic chemotherapy prior to T
cell collection
CAR T therapy in earlier lines of treatment earlier T cell collection in
high‐risk pts
Improving CAR‐T trafficking Combine with cytokine TRUCKs co‐expressing IL‐12, IL‐15, or IL‐18
Novel lymphodepletion approaches Higher dose fludarabine/cyclophosphamide
Alternative agents (oxaliplatin)
CD19 loss Novel CAR T targets scFVs specific for CD20, CD22, CD79b, BAFF‐R, kappa light chain,
ROR1
Dual antigen targeting Bispecific CAR T cells: LV20.19: anti‐CD19 +anti‐CD20 AUTO‐3:
anti‐CD19 +anti‐CD22
CAR T exhaustion Blocking immune checkpoint signaling Co‐administration of checkpoint inhibitors
Anti‐PD‐1 or anti‐PD‐L1 blocker secretion
PD‐1 gene silencing
PD‐1/CD28 “switch receptors”
Modulating downstream signaling Third‐generation CAR T cells
CD3 ITAM modulation (1XX)
Other immunomodulators Ibrutinib
Lenalidomide
Recruiting endogenous
immune cells
Local cytokine production TRUCKS co‐expressing IL‐12, IL‐15, or IL‐18
Antigen presenting cell licensing Armored CARs secreting CD40L
Toxicity Anti‐inflammatory agents Anakinra
Other immunomodulators Ibrutinib
Off‐switches Inducible Casp9
EGFR surface expression
CD20 expression
Reversible CAR T inhibition Dasatinib
Changes to CAR T design Hinge/linker changes—CD19‐BBz(86)
GM‐CSF gene silencing
Abbreviations: CAR, chimeric antigen receptor; GM‐CSF, granulocyte‐macrophage colony stimulating factor; ITAM, immunoreceptor tyrosine‐based
activation motif; scFV, single chain variable fragment.
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-
QUALLS AND SALLES
results in preclinical studies. In one preclinical study, inactivation
of the second and third immunoreceptor tyrosine‐based activation
motifs (ITAMs) on CD3ζ, leaving only the most proximal ITAM, led
to increased anti‐tumor activity and T cell persistence.
32
This
“1XX” CAR construct is currently being investigated in an ongoing
clinical trial.
The hinge and transmembrane domains also play a role in CAR
signaling. In one such example, the standard CD19‐BBz(71) product
utilized in tisa‐cel was modified with additional amino acids, length-
ening the extracellular and intracellular transmembrane domains.
33
The resultant CD19‐BBz(86) product retained cytolytic capacity
while exhibiting markedly decreased cytokine production as
compared to standard CD19‐BBz. A Phase I clinical trial of CD19‐
BBz(86) showed comparable antitumor efficacy with remarkably low
toxicity; no patients had greater than grade I CRS/ICANS, and there
were no significant elevations in serum cytokine levels after infusion.
The underlying mechanism for this functional change remains to be
elucidated, but does reinforce the dynamic role of hinge and trans-
membrane domains, and the potential for less toxic CAR T
constructs.
8.3
|
Alternative and dual‐targeted CAR T cells
One of the primary mechanisms of resistance to CD19‐directed CAR
T therapy is antigen escape via CD19 surface antigen loss (induced by
various molecular alterations in the CD19 gene). To address this,
alternative CARs with scFVs recognizing CD20, CD22, CD79b,
BAFF‐R, kappa light chain, and ROR1 have been developed and are in
various stages of preclinical and clinical development. Bispecific CAR
T cells targeting two surface antigens simultaneously may prevent
resistance via antigen escape, and clinical studies investigating these
therapies are underway. One such study of LV20.19 CAR T cells, with
bispecific CD19 and CD20 targeting, showed promising efficacy and
safety profile (ORR 82%, CR 64%).
24
Notably, none of the patients
who had progression or relapse had loss of CD19. Similarly encour-
aging results have been reported with AUTO‐3, a bispecific CAR T
expressing anti‐CD19 and anti‐CD22 CARs.
34
8.4
|
Armored CARs, TRUCKs, and other co‐
modifications
In addition to CAR modifications, T cell co‐modifications are being
investigated to overcome the immunosuppressive tumor microenvi-
ronment, stimulate intrinsic immune response and in some cases
deliver antitumor drugs in a localized fashion.
35
TRUCKs (T cells
Redirected for Universal Cytokine Killing) are CAR T cells engineered
to secrete cytokines such as IL‐12, IL‐15, or IL‐18. In preclinical
models these modifications have been shown to increase cytotoxicity
and CAR T cell expansion, increase resistance to Treg cell‐mediated
inhibition, and in some cases recruit endogenous immune cells to the
tumor microenvironment. CAR T cells expressing CD40 ligand
upregulate antigen presentation in B cell malignancies and activate
antigen‐presenting cells, and may facilitate a sustained endogenous
immune response against tumor. Other models have been developed
using various strategies to disrupt the PD‐1/PD‐L1 immune check-
point axis and disinhibit immune effector cells, including the CAR T
cells themselves.
Co‐modifications meant to mitigate toxicity have also been
developed. Mutations silencing the production of granulocyte‐
macrophage colony stimulating factor (GM‐CSF), which activates
FIGURE 1 Selected CAR T cell constructs currently in use or in development. Figure 1A,B are second‐generation constructs consistent
with tisa‐cel and axi‐cel, respectively. Third generation (Figure 1C) CAR T cells contain two costimulatory domains. The 1XX CAR construct
(Figure 1D) is genetically modified with activation of the second and third ITAMs, reducing redundant activation and downstream signaling.
Modifications to the hinge and transmembrane domains (Figure 1E) have been demonstrated to alter activation potential and cytokine
production. Dual‐targeted CAR T cells have also been developed either expressing a single CAR with two scFV domains targeting two separate
surface antigens (Figure 1F) or expressing two separate CARs with differing targets (Figure 1G). The figure was created with BioRender.com.
CAR, chimeric antigen receptor; ITAM, immunoreceptor tyrosine‐based activation motif
QUALLS AND SALLES
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109
monocytes and macrophages, appear to mitigate CRS while
improving efficacy in preclinical models.
In the event of significant CAR T‐related toxicity, mechanisms for
halting CAR T activity are under investigation. Engineered surface
expression of CD20 or EGFR allows monoclonal antibody‐mediated
killing of CAR T cells via rituximab or cetuximab, respectively. The
engineered “kill switch” protein iCasp9 can be activated through
administration of a small molecule that facilitates dimerization of
iCasp9 and results in CAR T cell apoptosis. Other approaches include
the use of small molecule therapy for reversible inhibition of CAR T
activity, as recently demonstrated in preclinical models with
dasatinib.
36
9
|
COMBINATION THERAPY
A number of clinical studies are underway evaluating the combina-
tion of established CAR T therapies with a number of potentially
additive or synergistic agents thought to enhance the antitumor ac-
tivity of CAR T cells, reduce T cell exhaustion, or mitigate toxicity.
Phase 1/2 trials investigating CAR T products including checkpoint
inhibitors, immunomodulators, and Bruton tyrosine kinase (BTK) in-
hibitors are ongoing. Other treatments intended to reduce the risk or
severity of CRS and neurotoxicity are also underway, with the anti‐
IL‐1R agent anakinra undergoing active clinical investigation.
Disruption of the PD‐1/PD‐L1 immune checkpoint through PD‐1
and PD‐L1 inhibitors has shown activity in many malignancies,
including Hodgkin lymphoma, though their activity in B‐cell NHL is
limited. There is interest in using checkpoint inhibitors alongside CAR
T therapy to reduce CAR T cell exhaustion and facilitate more robust
antitumor responses. One study showed that PD‐1 with pem-
brolizumab used as “rescue” for patients who progressed after CAR T
therapy showed CAR T re‐expansion in 9 of 12 patients, with an ORR
of 27%.
37
While modest, the fact that this therapy generated re-
sponses in patients who had otherwise failed CAR T therapy suggests
a role for checkpoint inhibitors. Concomitant therapy with check-
point inhibitors and CAR T is being investigated in a number of
clinical trials, with preliminary results showing adequate safety pro-
files. Larger studies are needed to determine whether such combi-
nations result in superior outcomes.
Concomitant administration of ibrutinib, a BTK inhibitor, has
been demonstrated in preclinical models to reduce CART‐related
cytokine production. A recent Phase I study of ibrutinib given
alongside CAR T therapy for ibrutinib‐refractory CLL showed an
similar response rates and lower CRS severity, with a trend toward
superior CAR T expansion, when compared to another cohort that
did not receive ibrutinib.
38
Larger prospective clinical trials in CLL
and NHL are ongoing to further evaluate these preliminary findings.
Preclinical data also suggest that immunomodulatory agents
such as lenalidomide may also enhance the anti‐tumor effects of CAR
T cells, and ongoing studies are evaluating the safety and efficacy of
this and other immunomodulatory agents alongside established CAR
T constructs.
10
|
CONCLUSIONS
CAR T therapy has revolutionized the management of patients with
B‐cell lymphoma. The applicability of CAR T is expected to expand to
include additional lymphoma subtypes, disease states, and phases of
treatment in the coming years. Challenges remain in overcoming
barriers to CAR T treatment, improving efficacy, and minimizing
toxicity. A number of promising solutions are already in preclinical
and early clinical development, with early data suggesting many safe
and effective CAR T regimens. Determining which of these CAR T
strategies are most effective in improving outcomes will become an
increasingly important question, particularly as they are largely
developed in parallel with few head‐to‐head comparisons. Outside of
the CAR T spectrum, other promising modalities, including bispecific
antibodies, are showing promising results, and determining when to
utilize CAR T over these other strategies presents another challenge.
Going forward, thoughtfully designed clinical trials comparing these
strategies, and further translational studies to understand the bio-
logical underpinnings of this novel technology, will be necessary to
ensure continued improvement in outcomes for patients with
lymphoma.
CONFLICT OF INTEREST
David Qualls has no conflicts of interest to disclose. Gilles Salles has
received in the last 12months financial compensations for partici-
pating to advisory boards or consulting from Abbvie, Beigene, BMS/
Celgene, Debiopharm, Genentech/Roche, Genmab, Incyte, Kite/
Gilead, Milteniy, Morphosys, Novartis, Velosbio
ORCID
Gilles Salles https://orcid.org/0000-0002-9541-8666
REFERENCES
1. Locke FL, Ghobadi A, Jacobson CA, et al. Long‐term safety and
activity of axicabtagene ciloleucel in refractory large B‐cell lym-
phoma (ZUMA‐1): a single‐arm, multicentre, phase 1–2 trial. Lancet
Oncol 2019;20(1):31‐42. https://doi.org/10.1016/S1470‐2045(18)
30864‐7.
2. Schuster SJ, Bishop MR, Tam CS, et al. Tisagenlecleucel in adult
relapsed or refractory diffuse large B‐cell lymphoma. N Engl J Med.
2019;380(1):45‐56. https://doi.org/10.1056/nejmoa1804980.
3. Abramson JS, Palomba ML, Gordon LI, et al. Lisocabtagene mar-
aleucel for patients with relapsed or refractory large B‐cell lym-
phomas (TRANSCEND NHL 001): a multicentre seamless design
study. Lancet. 2020;396(10254):839‐852. https://doi.org/10.1016/
S0140‐6736(20)31366‐0.
4. Crump M, Neelapu SS, Farooq U, et al. Outcomes in refractory
diffuse large B‐cell lymphoma: results from the international
SCHOLAR‐1 study. Blood. 2017;130(16):1800‐1808. https://doi.org/
10.1182/blood‐2017‐03‐769620.
5. Vitale C, Strati P. CAR T‐cell therapy for B‐cell non‐Hodgkin lym-
phoma and chronic lymphocytic leukemia: clinical trials and real‐
world experiences. Front Oncol. 2020;10:849. https://doi.org/
10.3389/fonc.2020.00849.
6. Wang M, Munoz J, Goy A, et al. KTE‐X19 CAR T‐cell therapy in
relapsed or refractory mantle‐cell lymphoma. N Engl J Med.
2020;382(14):1331‐1342. https://doi.org/10.1056/nejmoa1914347.
110
-
QUALLS AND SALLES
7. Nastoupil LJ, Jain MD, Feng L, et al. Standard‐of‐care axicabtagene
ciloleucel for relapsed or refractory large B‐cell lymphoma: results
from the US lymphoma CAR T consortium. J Clin Oncol.
2020;38(27):3119‐3128. https://doi.org/10.1200/JCO.19.02104.
8. Vercellino L, Di Blasi R, Kanoun S, et al. Predictive factors of early
progression after CAR T‐cell therapy in relapsed/refractory diffuse
large B‐cell lymphoma. Blood Adv. 2020;4(22):5607‐5615. https://
doi.org/10.1182/bloodadvances.2020003001.
9. Du M, Hari P, Hu Y, Mei H. Biomarkers in individualized manage-
ment of chimeric antigen receptor T cell therapy. Biomark Res.
2020;8(1):1‐13. https://doi.org/10.1186/s40364‐020‐00190‐8.
10. Fraietta JA, Lacey SF, Orlando EJ, et al. Determinants of response
and resistance to CD19 chimeric antigen receptor (CAR) T cell
therapy of chronic lymphocytic leukemia. Nat Med. 2018;24(5):
563‐571. https://doi.org/10.1038/s41591‐018‐0010‐1.
11. Rossi J, Paczkowski P, Shen YW, et al. Preinfusion polyfunctional
anti‐CD19 chimeric antigen receptor T cells are associated with
clinical outcomes in NHL. Blood. 2018;132(8):804‐814. https://doi.
org/10.1182/blood‐2018‐01‐828343.
12. Duell J, Lukic DS, Karg M, et al. Functionally defective T cells after
chemotherapy of B‐cell malignancies can Be activated by the tetra-
valent bispecific CD19/CD3 antibody AFM11. J Immunother. 2019;
42(5):180‐188. https://doi.org/10.1097/CJI.0000000000000267.
13. Jacobson C, Chavez JC, Sehgal AR, et al. Primary analysis of Zuma‐5:
a phase 2 study of axicabtagene ciloleucel (Axi‐Cel) in patients with
relapsed/refractory (R/R) indolent non‐Hodgkin lymphoma (iNHL).
Blood. 2020;136(Suppl 1):40‐41. https://doi.org/10.1182/BLOOD‐
2020‐136834.
14. Palomba ML, Gordon LI, Siddiqi T, et al. Safety and preliminary
efficacy in patients with relapsed/refractory mantle cell lymphoma
receiving lisocabtagene maraleucel in transcend NHL 001.
Blood. 2020;136(Suppl 1):10‐11. https://doi.org/10.1182/blood‐
2020‐136158.
15. Siddiqi T, Soumerai JD, Dorritie KA, et al. Updated follow‐up of
patients with relapsed/refractory chronic lymphocytic leukemia/
small lymphocytic lymphoma treated with lisocabtagene maraleucel
in the phase 1 monotherapy cohort of transcend CLL 004, including
high‐risk and ibrutinib‐treated patients. Blood. 2020;136(Suppl
1):40‐41. https://doi.org/10.1182/BLOOD‐2020‐140491.
16. Fowler NH, Dickinson M, Dreyling M, et al. Efficacy and safety
of tisagenlecleucel in adult patients with relapsed/refractory
follicular lymphoma: interim analysis of the phase 2 Elara trial.
Blood. 2020;136(Suppl 1):1‐3. https://doi.org/10.1182/blood‐2020‐
138983.
17. Ramos CA, Grover NS, Beaven AW, et al. Anti‐CD30 CAR‐T cell
therapy in relapsed and refractory Hodgkin lymphoma. J Clin
Oncol. 2020;38(32):3794‐3804. https://doi.org/10.1200/JCO.20.
01342.
18. Frigault MJ, Maus MV, Dietrich J, et al. Tisagenlecleucel CAR T‐cell
therapy in secondary CNS lymphoma. Blood. 2019;134(11):860‐866.
https://doi.org/10.1182/blood.2019001694.
19. Bennani NN, Maurer MJ, Nastoupil LJ, et al. Experience with axi-
cabtagene ciloleucel (Axi‐cel) in patients with secondary CNS
Involvement: results from the US lymphoma CAR T consortium.
Blood. 2019;134(Suppl 1):763‐763. https://doi.org/10.1182/blood‐
2019‐129097.
20. Locke FL. CAR T‐cell therapy hopes to move to second line in diffuse
large B‐cell lymphoma | the hematologist | American Society of
Hematology. Hematol. 2020;17(6).
21. Neelapu SS, Dickinson M, Ulrickson ML, et al. Interim analysis of
ZUMA‐12: a phase 2 study of axicabtagene ciloleucel (Axi‐Cel) as
first‐line therapy in patients (Pts) with high‐risk large B cell lym-
phoma (LBCL). Blood. 2020;136(Suppl 1):49‐49. https://doi.org/
10.1182/blood‐2020‐134449.
22. Riedell PA, Walling C, Nastoupil LJ, et al. A multicenter retrospective
analysis of outcomes and toxicities with commercial axicabtagene
ciloleucel and tisagenlecleucel for relapsed/refractory aggressive
B‐cell lymphomas. Biol Blood Marrow Transpl. 2020;26(3):S41‐S42.
https://doi.org/10.1016/j.bbmt.2019.12.108.
23. Borchmann P, Jühling A, Gödel P, et al. Phase I trial of MB‐
CART2019.1, a novel CD20 and CD19 targeting tandem chimeric
antigen receptor, in patients with relapsed or refractory B‐cell non‐
Hodgkin lymphoma. Blood. 2020;136(Supplement 1):48‐48. https://
doi.org/10.1182/blood‐2020‐136067.
24. Shah NN, Johnson BD, Schneider D, et al. Bispecific anti‐CD20, anti‐
CD19 CAR T cells for relapsed B cell malignancies: a phase 1 dose
escalation and expansion trial. Nat Med. 2020;26(10):1569‐1575.
https://doi.org/10.1038/s41591‐020‐1081‐3.
25. Neelapu SS, Munoz J, Locke FL, et al. First‐in‐human data of ALLO‐
501 and ALLO‐647 in relapsed/refractory large B‐cell or follicular
lymphoma (R/R LBCL/FL): ALPHA study. J Clin Oncol.
2020;38(15_suppl):8002‐8002. https://doi.org/10.1200/jco.2020.38.
15_suppl.8002.
26. Liu E, Marin D, Banerjee P, et al. Use of CAR‐transduced natural
killer cells in CD19‐positive lymphoid tumors. N Engl J Med.
2020;382(6):545‐553. https://doi.org/10.1056/NEJMoa1910607.
27. Brentjens RJ, Rivière I, Park JH, et al. Safety and persistence of
adoptively transferred autologous CD19‐targeted T cells in patients
with relapsed or chemotherapy refractory B‐cell leukemias. Blood.
2011;118(18):4817‐4828. https://doi.org/10.1182/blood‐2011‐04‐
348540.
28. Bechman N, Maher J. Lymphodepletion strategies to potentiate
adoptive T‐cell immunotherapy – what are we doing; where are we
going? Expert Opin Biol Ther. 2011;18:1‐11. https://doi.org/10.1080/
14712598.2021.1857361.
29. Hirayama AV, Gauthier J, Hay KA, et al. The response to lymphode-
pletion impacts PFS in patients with aggressive non‐Hodgkin
lymphoma treated with CD19 CAR T cells. Blood. 2019;133(17):1876‐
1887. https://doi.org/10.1182/blood‐2018‐11‐887067.
30. Srivastava S, Furlan SN, Jaeger‐Ruckstuhl CA, et al. Immunogenic
chemotherapy enhances recruitment of CAR‐T cells to lung tumors
and improves antitumor efficacy when combined with checkpoint
blockade. Canc Cell. December 2020. https://doi.org/10.1016/j.
ccell.2020.11.005.
31. Ramos CA, Rouce R, Robertson CS, et al. Vivo fate and activity of
second‐versus third‐generation CD19‐specific CAR‐T cells in B cell
non‐Hodgkin's lymphomas. Mol Ther. 2018;26(12):2727‐2737.
https://doi.org/10.1016/j.ymthe.2018.09.009.In
32. Feucht J, Sun J, Eyquem J, et al. Calibration of CAR activation potential
directs alternative T cell fates and therapeutic potency. Nat
Med. 2019;25(1):82‐88. https://doi.org/10.1038/s41591‐018‐
0290‐5.
33. Ying Z, Huang XF, Xiang X, et al. A safe and potent anti‐CD19 CAR T
cell therapy. Nat Med. 2019;25(6):947‐953. https://doi.org/10.1038/
s41591‐019‐0421‐7.
34. Osborne W, Marzolini M, Tholouli E, et al. Phase I Alexander study
of AUTO3, the first CD19/22 dual targeting CAR T cell therapy, with
pembrolizumab in patients with relapsed/refractory (r/r) DLBCL.
J Clin Oncol. 2020;38(15_suppl):8001. https://doi.org/10.1200/
jco.2020.38.15_suppl.8001.
35. Rafiq S, Hackett CS, Brentjens RJ. Engineering strategies to over-
come the current roadblocks in CAR T cell therapy. Nat Rev Clin
Oncol. 2020;17(3):147‐167. https://doi.org/10.1038/s41571‐019‐
0297‐y.
36. Mestermann K, Giavridis T, Weber J, et al. The tyrosine kinase in-
hibitor dasatinib acts as a pharmacologic on/off switch for CAR T
cells. Sci Transl Med. 2019;11(499). eaau5907. https://doi.org/
10.1126/scitranslmed.aau5907.
QUALLS AND SALLES
-
111
37. Chong EA, Svoboda J, Dwivedy Nasta S, et al. Sequential anti‐CD19
directed chimeric antigen receptor modified T‐cell therapy
(CART19) and PD‐1 blockade with pembrolizumab in patients with
relapsed or refractory B‐cell non‐Hodgkin lymphomas. Blood.
2018;132(Suppl 1):4198. https://doi.org/10.1182/blood‐2018‐99‐
119502.
38. Gauthier J, Hirayama AV, Purushe J, et al. Feasibility and efficacy of
CD19‐targeted CAR T cells with concurrent ibrutinib for CLL after
ibrutinib failure. Blood. 2020;135(19):1650‐1660. https://doi.org/
10.1182/blood.2019002936.
How to cite this article: Qualls D, Salles G. Optimizing CAR T
cell therapy in lymphoma. Hematological Oncology.
2021;39(S1):104–112. https://doi.org/10.1002/hon.2844
112
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Received: 3 March 2021
DOI: 10.1002/hon.2858
SUPPLEMENT ARTICLE
Bispecific antibodies for the treatment of lymphomas:
Promises and challenges
Stephen J. Schuster
1,2
1
Perelman School of Medicine, University of
Pennsylvania, Philadelphia, Pennyslvania, USA
2
Lymphoma Program & Lymphoma
Translational Research, Abramson Cancer
Center, University of Pennsylvania,
Philadelphia, Pennyslvania, USA
Correspondence
Stephen J. Schuster, Perelman Center for
Advanced Medicine, 34th & Civic Center
Blvd., 12 Fl. South Pavilion, Philadelphia, PA
19104, USA.
Email: stephen.schuster@pennmedicine.
upenn.edu
Abstract
The potential of bispecific antibodies to direct antigen‐specific T cell‐mediated
cytotoxicity toward malignant cells bearing a target antigen was recognized over
35 years ago. Generally, this is accomplished by combining a T‐cell receptor‐specific
monoclonal antibody or monoclonal antibody‐derived fragment that is capable of
activating and expanding resting T cells with a second monoclonal antibody or
monoclonal antibody fragment directed against a tumor target antigen. Bispecific
antibodies induce effector T cells that bind to tumor cells independently of their T‐
cell receptor specificity and without the requirement of MHC‐mediated antigen
presentation, focusing effector T‐cell cytotoxicity on tumor cells bearing the target
antigen. The therapeutic efficacy of this approach for treatment of relapsed or re-
fractory B‐cell lymphomas was first demonstrated with blinatumomab, a single
molecule comprised of two linked single‐chain variable fragments with binding
specificities for CD19 and CD3. The recent demonstration that chimeric antigen
receptor (CAR) modified T cells can achieve very durable remissions in some pa-
tients with relapsed or refractory B‐cell lymphomas, as well as the potential efficacy
of bispecific antibodies in CAR T cell failures, has rekindled interested in bispecific
antibodies as a T cell‐mediated therapeutic approach. We review the early results of
phase 1 clinical trials of bispecific antibodies targeting CD20 on B cells and engaging
T cells via CD3 in 1:1 or 2:1 CD20:CD3 Fab formats for treatment of relapsed or
refractory B‐cell lymphomas.
KEYWORDS
bispecific antibody, blinatumomab, glofitamab, immunotherapy, mosunetuzumab,
odronextumab
The term bispecific antibody (bsAb) refers to an antibody or an
antibody‐derived protein construct that has binding specificities for
two different antigens. In humans and most mammals, all naturally
occurring monomeric antibodies are bivalent with respect to number
of antigen‐binding sites. These two binding sites are almost always
monospecific (i.e., having the same antigen‐binding specificity at each
of an antibody's two antigen‐binding regions). In comparison, bispe-
cific antibodies combine two different monospecific antigen‐binding
regions, or variable regions, from different antibodies to achieve a
single antibody or antibody‐derived molecule with bispecific antigen
binding.
In 1960, nearly simultaneous with Porter's seminal observation
that digestion of rabbit antibody with papain yielded two almost
identical univalent antigen‐binding fragments (Fab’) per antibody
molecule, Nisonoff and coworkers observed that pepsin digestion
produced a single bivalent antigen‐binding fragment [F(ab’)2] which,
after treatment with a disulfide‐splitting reagent, yielded two univa-
lent Fab’ fragments that could be recombined into an F(ab’)2 by
Hematological Oncology. 2021;39(S1):113–116. wileyonlinelibrary.com/journal/hon © 2021 John Wiley & Sons Ltd.
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113
FIGURE 1 Antibody fragments—the building blocks of bispecific antibodies
TABLE 1Structure of selected bi‐specific antibodies
114
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SCHUSTER
oxidation of sulfhydryl groups.
1,2
(Figure 1). Immediately recognizing
the significance of their observations, these investigators speculated,
“It should also be of interest to attempt to prepare antibody of mixed
specificity.”
2
Soon afterwards in 1964, proof of this concept was
established in an elegant series of experiments by Fudenberg et al. that
demonstrated the successful construction, starting with monospecific
rabbit antisera, of a single “bivalent hybrid antibody” or more precisely
an F(ab’)2 with bispecific binding to both bovine gamma globulin and
chicken ovalbumin.
3
Thus began the development of bispecific anti-
bodies and their application for diagnostic and therapeutic purposes.
The confluence of subsequent discoveries in basic and tumor
immunology, technical innovations in laboratory immunology, and
development of recombinant DNA technology over the next 50 years
resulted in a vast variety of approaches for creating antibodies or
single‐molecule antibody derivatives of “mixed specificity.” Using
combinations of immunoglobulin‐derived proteins or genetic mod-
ules designed to modify the specificity, valency, size, flexibility,
pharmacokinetic and pharmacodynamic properties, and to enhance
large scale production, a panoply of bsAb formats has evolved and
continues to evolve. Current bsAb formats include full antibody‐
sized, antibody fragment‐sized, and complex larger than antibody
formats, including bivalent and multivalent formats (reviewed in
Brinkmann and Kontermann
4
).
In 1985, the feasibility of directing T cells to effect antigen‐
specific cytotoxicity toward cells bearing the target antigen of
choice by using “hybrid antibodies” (in this case, chemically linked
monoclonal antibodies) was demonstrated in vitro.
4–6
At that time, it
was recognized that these antibody “heteroconjugates” could (1)
overcome MHC‐restricted antigen presentation to cytotoxic T cells,
(2) eliminate the problem of rejection of transplanted effector cells,
and (3) focus effector T‐cell cytotoxicity on cells bearing the target
antigen. This was achieved by combining a T‐cell receptor specific
monoclonal antibody capable of activating and expanding resting T
cells, as well as inducing effector T cells, together with a second
monoclonal antibody directed against any chosen target antigen.
In 2008, Bargou et al. reported the first use of a bsAb for treat-
ment of lymphomas, namely, blinatumomab.
7
Using two single‐chain
variable fragments (Fv, Figure 1; Table 1) with binding specificities
for CD19 +CD3 linked by a serine‐glycine peptide and administered
by continuous intravenous infusion because of its small size and rapid
clearance, responses to blinatumomab were reported in patients with
relapsed follicular lymphoma, mantle cell lymphoma, and chronic
lymphocytic leukemia. Along with these objective responses, the first
observations of what are now recognized syndromes of special in-
terest related to T‐cell engaging therapies—cytokine release syn-
drome (CRS) and immune effector cell‐associated neurotoxicity
syndrome (ICANS)—were reported. Subsequent multicenter phase 1
and phase 2 studies in patients with relapsed or refractory B‐cell non‐
Hodgkin lymphomas of various histologies (N=76) and diffuse large B‐
cell lymphomas (N=25) were completed (Figure 2).
8–10
These studies
confirmed the clinical activity of blinatumomab with overall response
rates of 64% and 43% for varied B‐cell lymphomas and for diffuse large
B‐cell lymphoma cohorts, respectively; remarkably, 6 of 25 patients
treated at the effective dose of at least 60 µg/m
2
per day remain in
ongoing remissions beyond 5 years (3 with follicular lymphoma, 2 with
mantle cell lymphoma, and 1 with diffuse large B‐cell lymphoma).
8
The
acute toxicity profile of blinatumomab, especially neurologic adverse
events, is considerable but manageable, and no late toxicities have
FIGURE 2 Summary of selected bi‐specific antibodies: safety and efficacy
SCHUSTER
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115
been observed. In 2014, blinatumomab was approved by the US FDA
for treatment of Philadelphia chromosome‐negative relapsed or re-
fractory B‐cell precursor acute lymphoblastic leukemia (ALL); its
approval was expanded in 2018 to include minimal residual disease‐
positive B‐cell precursor ALL.
Although the early results for blinatumomab were promising and
supported further development of the bsAb approach for treatment of
B‐cell lymphomas, the emergence of CD19‐directed chimeric antigen
receptor (CAR) modified T‐cell therapies (CAR T) over the last 10
years briefly eclipsed the ongoing development of bsAbs.
11,12
How-
ever, the observations that CAR T cells are capable of achieving very
durable remissions in some patients with relapsed or refractory B‐cell
lymphomas, as well as the potential efficacy of bsAb in CAR T cell
failures, supported the T cell‐mediated approach to therapy, whether
by CAR T or bsAb, and ultimately rekindled interested in bsAbs.
Currently, a variety of bsAbs are under development as therapy
for B‐cell lymphomas. The early results of phase 1 bsAb clinical trials
are summarized in Table 1and Figure 2. These bsAbs target CD20
on B cells and engage T cells via CD3 in a 1:1 or 2:1 CD20:CD3 Fab
format. They are full size antibody derivatives and thus have phar-
macokinetic profiles that allow intermittent dosing. In general,
neurotoxicity is significantly less frequent than observed with CD19‐
directed CAR T or blinatumomab therapies. Overall response rates
range from 60 to 90% with complete response rates from 40 to 60%
in relapsed or refractory indolent and follicular lymphomas.
13–15
In
relapsed or refractory large B‐cell lymphomas, overall response rates
range from 37% to 90% with complete response rates from 19% to
55%. Importantly, these bsAbs appear to have activity in patients
failing CD19‐directed CAR T therapy. However, follow‐up for these
new bsAbs is short and the durability of responses remains to be
established.
While proof of principle for bsAbs has been clearly demon-
strated, optimal clinical use of bsAbs in B‐cell lymphomas remains to
be established. As we wait for the early phase clinical trials to com-
plete accrual and to mature, we can expect bsAb combinations to be
explored in the next generation of bsAb clinical trials.
CONFLICT OF INTEREST
Schuster is associated with AlloGene (Ad Board), AstraZeneca (Ad
Board), BeiGene (Ad Board) Celgene/BMS (Ad Board, Consulting,
Steering committee), Genentech/Roche (Ad Board, Consulting,
Steering committee, Research Grant), Incyte (Ad Board), Janssen (Ad
Board), Legend Biotech (Ad Board), Loxo Oncology (Ad Board,
Consulting), Novartis (Ad Board, Consulting, Steering committee,
Research Grant), and Regeneron (Ad Board).
DATA AV1AILABILITY STATEMENT
Data sharing is not applicable to this article as no new data were
created or analyzed in this study.
REFERENCES
1. Porter RR. Separation and isolation of fractions of rabbit gamma‐
globulin containing the antibody and antigenic combining sites. Na-
ture. 1958;182(4636):670‐671.
2. Nisonoff A, Wissler FC, Lipman LN. Properties of the major
component of a peptic digest of rabbit antibody. Science. 1960;
132(3441):1770‐1771.
3. Fudenberg HH, Drews G, Nisonoff A. Serologic demonstration of
dual specificity of rabbit bivalent hybrid antibody. J Exp Med. 1964;
119(1):151‐166.
4. Brinkmann U, Kontermann RE. The making of bispecific antibodies.
mAbs. 2017;9(2):182‐212.
5. Staerz UD, Kanagawa O, Bevan MJ. Hybrid antibodies can target
sites for attack by T cells. Nature. 1985;314(6012):628‐631.
6. Perez P, Hoffman RW, Shaw S, Bluestone JA, Segal DM. Specific
targeting of cytotoxic T cells by anti‐T3 linked to anti‐target cell
antibody. Nature. 1985;316:354‐356.
7. Bargou R, Leo E, Zugmaier G, et al. Tumor regression in cancer pa-
tients by very low doses of a T cell‐engaging antibody. Science.
2008;321(5891):974‐977.
8. Dufner V, Sayehli CM, Chatterjee M, et al. Long‐term outcome of
patients with relapsed/refractory B‐cell non‐Hodgkin lymphoma
treated with blinatumomab. Blood Adv. 2019;3(16):2491‐2498.
9. Goebeler M‐E, Knop S, Viardot A, et al. Bispecific T‐cell engager
(BiTE) antibody construct blinatumomab for the treatment of pa-
tients with relapsed/refractory non‐Hodgkin lymphoma: final results
from a phase I study. J Clin Oncol. 2016;34(10):1104‐1111.
10. Viardot A, Goebeler M‐E, Hess G, et al. Phase 2 study of the bis-
pecific T‐cell engager (BiTE
®
) antibody blinatumomab in relapsed/
refractory diffuse large B‐cell lymphoma. Blood. 2016;127(11):
1410‐1416.
11. Cappell KM, Sherry RM, Yang JC, et al. Long‐term follow‐up of anti‐
CD19 chimeric antigen receptor T‐cell therapy. J Clin Oncol.
2020;38(32):3805‐3815.
12. Chong EA, Ruella M, Schuster SJ. Five‐year outcomes for refractory
B‐cell lymphomas with CAR T‐cell therapy. N Engl J Med.
2021;384(7):673‐674.
13. Schuster SJ, Bartlett NL, Assouline S, et al. Mosunetuzumab induces
complete remissions in poor prognosis non‐Hodgkin lymphoma pa-
tients, including those who are resistant to or relapsing after
chimeric antigen receptor T‐cell (CAR‐T) therapies, and is active in
treatment through multiple lines. Blood. 2019;134(Suppl 1). ASH
Plenary abstract 6.
14. Hutchings M, Carlo‐Stella C, Bachy E, et al. Glofitamab step‐up dosing
induces high response rates in patients with hard‐to‐treat refractory
or relapsed non‐Hodgkin lymphoma. Blood. 2020;136(Supplement
1):46‐48.
15. Bannerji R, Allan JN, Arnason JE, et al. Odronextamab (REGN1979),
a human CD20 x CD3 bispecific antibody, induces durable, complete
responses in patients with highly refractory B‐cell non‐Hodgkin
lymphoma, including patients refractory to CAR T therapy. Blood.
2020;136(Suppl 1):42‐43.
How to cite this article: Schuster SJ. Bispecific antibodies for
the treatment of lymphomas: Promises and challenges.
Hematological Oncology. 2021;39(S1):113–116. https://doi.
org/10.1002/hon.2858
116
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